GA29144

Principal Investigator: John  Valentine
Keywords: Crohns , Etrolizumab Department: Gastroenterology
IRB Number: 00080265 Co Investigator:  
Specialty: Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis
Recruitment Status: Recruiting

Contact Information

Heather Munk
heather.munk@hsc.utah.edu
801-587-9092

Brief Summary

2. OBJECTIVES
2.1 EFFICACY OBJECTIVES
Separate primary objectives will be evaluated for the FDA and for the EMA, and potentially other health authorities outside the United States (ex-U.S.). Each primary objective for one region will be assessed as a secondary objective for the other region (see Section 2.1.1).
Analyses of remission will use the Crohn’s Disease Activity Index (CDAI), which is a composite index with weighted domains that quantifies the global disease severity in a single numerical score (Best et al. 1979), and the Patient-Reported Outcomes-2 score (PRO2), which is a composite score for liquid/soft-stool frequency and abdominal pain (derived from the sum of the 7-day average scores for each item after multiplying each by their respective CDAI weighting; Khanna et al. 2014).
Analyses of endoscopic improvement will use the Simple Endoscopic Index for Crohn’s Disease (SES-CD); this is the summed score of four endoscopic variables that are rated in 5 ileocolonic segments of the bowel (Daperno et al. 2004).
2.1.1 Primary Objectives
The primary efficacy objectives for the U.S. are:
Induction Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing PRO2 remission, defined as a PRO2 score ≤ 11 at the end of the Induction Phase (Week 14)
Maintenance Phase
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining PRO2 remission at 1 year of maintenance treatment (Week 66) among patients who achieved PRO2 remission at the end of the Induction Phase (Week 14)
The primary efficacy objectives for the ex-U.S. are:
Induction Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing CDAI remission, defined as a CDAI score < 150 at the end of the Induction Phase (Week 14)
Maintenance Phase
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining CS-free CDAI remission for 1 year (52 weeks) among patients who achieved sustained CDAI remission at the end of the Induction Phase (Weeks 10 and 14)
2.1.2 Secondary Objectives
The global, secondary efficacy objectives are:
Induction Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing endoscopic improvement at Week 14, defined as a ≥50% reduction from the baseline SES-CD score
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing CDAI-100 response, defined as a decrease of at least 100 points from the baseline CDAI score at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in achieving sustained induction of CDAI remission at Weeks 10 and 14
• To evaluate change in patient−reported health-related quality of life (HRQOL) from baseline to Week 14 as assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ)
• To evaluate the reduction in CD signs and symptoms achieved by etrolizumab dose regimens compared with placebo at Week 14 as assessed by the Crohn’s Disease Patient-Reported Outcome Signs and Symptoms (CD-PRO/SS) measure
Maintenance Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in achieving endoscopic improvement at Week 66 (compared with endoscopic score at Week 0), among patients achieving CDAI-70 response (defined as a decrease of at least 70 points from the baseline CDAI score) at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining CDAI remission at Week 66, among patients achieving CDAI remission at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in achieving CDAI remission at Week 66, among patients achieving CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in achieving CDAI-100 response at Week 66 (compared with CDAI at Week 0) among patients achieving CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in achieving durable CDAI remission during 1 year of maintenance therapy (i.e., CDAI remission at ≥ 6 of the 8 CDAI-assessment visits which are conducted during the Maintenance Phase at Weeks 24, 28, 32, 44, 56, 66, 70, and 74) among patients achieving CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining CS free CDAI remission for 24 weeks at Week 66, among patients achieving CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining CS-free CDAI remission for 24 weeks at Week 66, among patients achieving CDAI remission at Weeks 10 and 14
• To evaluate the change in patient-reported HRQOL from baseline to Week 66 as assessed by the IBDQ among patients achieving CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining endoscopic improvement at Week 66 among patients achieving endoscopic improvement and CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in achieving resolution of mucosal inflammation (i.e., SES-CD score of 0) by Week 66, among patients achieving CDAI-70 response at Week 14
• To evaluate change in CD signs and symptoms from baseline to Week 66 as assessed by the CD-PRO/SS measure, among patients achieving CDAI-70 response at Week 14
The secondary efficacy objectives for the U.S. are:
Induction Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing CDAI remission, defined as a CDAI score < 150 at the end of the Induction Phase (Week 14)
Maintenance Phase
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining CS-free CDAI remission for 1 year (52 weeks) among etrolizumab-treated patients who achieved sustained CDAI remission at the end of the Induction Phase (Weeks 10 and 14)
The secondary efficacy objectives for the ex-U.S. are:
Induction Phase
• To evaluate the efficacy of etrolizumab dose regimens compared with placebo in inducing PRO2 remission, defined as a PRO2 score ≤ 11 at the end of the Induction Phase (Week 14)
Maintenance Phase
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining PRO2 remission at 1 year of maintenance treatment (Week 66) among patients who achieved PRO2 remission at the end of the Induction Phase (Week 14)
2.1.3 Exploratory Objectives
The exploratory efficacy objectives for the study are:
• To evaluate the efficacy of etrolizumab compared with placebo in maintaining endoscopic improvement at Week 66 among patients who achieved endoscopic improvement and CDAI-70 response at Week 14
• To evaluate the efficacy of etrolizumab compared with placebo in reducing fecal calprotectin levels at the end of the Induction and Maintenance Phases
• To evaluate the efficacy of etrolizumab compared with placebo in reducing C reactive protein (CRP) levels at the end of the Induction and Maintenance Phases
• To evaluate the time from Week 14 until experiencing major CD-related events (including hospitalizations, bowel surgeries and non-study procedures)
• To evaluate the effect of etrolizumab compared with placebo on the closure of draining fistulas
• To evaluate patient-reported IBDQ scores after 52-weeks of CS-free maintenance treatment
In addition to analyses addressing the above objectives, resource utilization and other patient reported outcome analyses will be undertaken using tools including, but not limited, to the EuroQOL Five Dimension Questionnaire (EQ-5D).
2.2 SAFETY OBJECTIVES
The safety objectives for this study are:
• To evaluate the overall safety and tolerability of etrolizumab compared with placebo during Induction and Maintenance Phases of therapy
• To evaluate the incidence and severity of infection-related adverse events
• To evaluate the incidence of malignancies
• To evaluate the incidence and severity of immunogenic responses (anti-therapeutic antibodies [ATAs])
• To evaluate the incidence and severity of hypersensitivity reaction events
2.3 PHARMACOKINETIC OBJECTIVES
The PK objectives for this study are:
• To evaluate etrolizumab serum concentrations at the end of the Induction Phase (Week 14) and at several predose time points when at steady state during the Maintenance Phase in patients who are re-randomized to etrolizumab
• To characterize the interindividual variability and potential covariate effects on etrolizumab serum exposure
• To investigate the relationship between serum exposure and CDAI-70 response and CDAI remission during the induction and maintenance treatment phases
• To characterize the PK profile of etrolizumab in patients with CD and the relationship between serum exposure of etrolizumab and β7 receptor occupancy by etrolizumab on peripheral blood T and B lymphocytes subsets (in a PK/PD substudy)
2.4 EXPLORATORY PHARMACODYNAMIC AND DIAGNOSTIC BIOMARKER OBJECTIVES
The exploratory PD and diagnostic biomarker objectives for this study are:
• To evaluate the relationship between baseline colonic mucosal and/or blood biomarkers and response to etrolizumab, including but not limited to the αE-integrin
• To evaluate the PD effects on colonic mucosal and/or peripheral blood biomarkers following treatment with etrolizumab
• To evaluate β7 receptor occupancy by etrolizumab on peripheral blood T and B lymphocyte subsets in a PK/PD substudy

Inclusion Criteria

4.1.1 Inclusion Criteria
Patients must meet the following criteria for study entry:
• Able and willing to provide written informed consent
• 18−80 years of age at time of consent
• For women who are not postmenopausal (at least 12 months of non−therapy-induced amenorrhea) or surgically sterile (e.g., absence of ovaries and/or uterus): agreement to remain abstinent or use a highly effective method of contraception (e.g., combined oral contraceptive pill or transdermal patch, spermicide and barrier [condoms], intrauterine device, implants for contraception, injections for contraception [with prolonged release], hormonal vaginal device, sterilization, or surgical tubal ligation for the duration of the study [i.e., during the treatment period and for at least 24 weeks after the last dose of study drug] see Appendix 4)
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
• For men: agreement to remain abstinent or use a condom, as well as not donate sperm during the treatment period and for at least 24 weeks after the last dose of study drug
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods for the partner) and withdrawal are not acceptable methods of contraception.
• Diagnosis of CD based on clinical, histopathological, and endoscopic evidence established ≥ 3 months prior to screening visit.
The Medical Monitor should be consulted in cases where CD was established at least 6 months prior to screening and a histopathology report, is not available. The eligibility of the patient will be considered based on the weight of evidence supporting diagnosis and excluding other potential diagnoses.
• Moderately to severely active disease defined in the Screening Phase by:
Clinical signs and symptoms resulting in a CDAI score of ≥ 220 to ≤ 480 calculated on the day of randomization, requiring a minimum of 4 days of e-diary PRO data from the 7 days prior to randomization AND
A PRO2 score ≥ 14 calculated on the day of randomization, requiring a minimum of 4 days of e-diary PRO data from the 7 days prior to randomization (applicable to Cohort 3, the pivotal cohort, only) AND
The presence of active inflammation on screening ileocolonoscopy defined as a SES-CD score of ≥ 7 or ≥ 4 in cases of isolated ileitis or post-ileocecal resection as determined by the central read model
• Involvement of ileum and/or colon with at least four colonic segments traversable by a pediatric endoscope or three segments (colon and/or ileum) for patients who have undergone a bowel resection for CD
• Meets the following surveillance colonoscopy requirements:
Surveillance was undertaken at screening or ≤ 12 months prior in patients with colonic disease for ≤ 10 years (regardless of any risk factors for bowel cancer).
Surveillance was undertaken at screening or ≤ 5 years prior in patients with colonic disease for ≤ 10 years who have risk factors for bowel cancer.
(Note- local colonic surveillance guidelines can be followed if patients have no risk factors and colonic disease for ≤ 10 years.)
• Have experienced intolerance, refractory disease, or no response (as defined below) to at least one of the following therapies within 5 years from screening:
CS Therapy
Refractory:
Has signs/symptoms of persistently active disease despite a history of at least one 4-week induction regimen including a dose equivalent to ≥ 30 mg/day prednisone for 2 weeks if oral or 1 week if IV or ≥ 9 mg/day
oral budesonide.
Intolerance to CS therapy:
History including but not limited to Cushing’s syndrome, osteopenia/osteoporosis, hyperglycemia, insomnia, and infection
IS Therapy
Refractory:
Has signs/symptoms of persistently active disease despite a history of at least one 12-week regimen of oral AZA (≥ 1.5 mg/kg) or 6-MP (≥ 0.75 mg/kg) or MTX (≥15 mg/week)
Intolerance to 6-MP, AZA, and/or MTX:
History of intolerance to  (including but not limited to infection, nausea/vomiting, abdominal pain, pancreatitis, liver function test abnormalities, lymphopenia, and thiopurine methyltransferase genetic polymorphism)
Anti-TNF Therapy:
Inadequate primary non-response:
Did not respond (as evidenced by persistent signs/symptoms related to CD after receiving ≥2 induction doses of either infliximab [≥5 mg/kg] or adalimumab [160 mg/80 mg or 80 mg/40 mg] or certolizumab pegol [≥ 400 mg])
Inadequate secondary non-response:
Initially responded to induction therapy with infliximab (≥5 mg/kg) or adalimumab (≥ 40 mg) or certolizumab pegol (≥ 400 mg) but experienced signs/symptoms related to recurrence of CD during maintenance
Intolerance:
Experienced a significant injection-site reaction, congestive heart failure, infection, or other condition that precluded continuing use of anti-TNF therapy at any time
 

Exclusion Criteria

4.1.2 Exclusion Criteria
Patients meeting any of the following criteria will be excluded from study entry.
Exclusion Criteria Related to Gastrointestinal Health
• Has undergone subtotal colectomy with ileorectal anastomosis or has undergone total colectomy
• Short-bowel syndrome
• Has an ileostomy or colostomy
• Has evidence of fixed stenosis or small-bowel stenosis with prestenotic dilation that precludes adequate endoscopic assessment of the bowel
• Diagnosis of UC or indeterminate colitis
• Suspicion of ischaemic colitis, radiation colitis, or microscopic colitis
• Evidence of abdominal or perianal abscess
• Sinus tract with evidence for infection (e.g., purulent discharge) in the clinical judgment of the investigator. Fistulas related to Crohn’s disease are not exclusionary.
• Expected to require surgery to manage CD-related complications during the study
• A history or evidence of adenomatous colonic polyps that have not been removed
• Past or present disease-related colonic mucosal dysplasia
 
Exclusion Criteria Related to Prior or Concomitant Therapy
• Any of the following treatments for CD within ≤ 128 weeks prior to randomization:
Adalimumab
Certolizumab pegol
Infliximab
Ustekinumab

• Any prior treatment with anti-adhesion molecules (e.g., anti-MAdCAM-1)

• Any prior treatment with etrolizumab or other anti-integrin agents (including vedolizumab, natalizumab, and efalizumab)

• Prior treatment with T cell− or B cell−depleting agents (e.g., rituximab, alemtuzumab, or visilizumab) within ≤ 12 months prior to randomization, with the exception of AZA and 6-MP.
• Any investigational treatment that included investigational vaccines within 12 weeks prior to randomization in the study or five half-lives of the investigational product, whichever is greater
• 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)
• Treatment with corticosteroid enemas/suppositories and/or topical (rectal) 5-aminiosalicylate (5-ASA) preparations ≤2 weeks prior to randomization
• Continued tube feeding, defined formula diets, and/or parenteral alimentation/nutrition as treatment for CD ≥ 3 weeks prior to randomization
• Expectation of tube feeding, defined formula diets, and/or parenteral alimentation/nutrition as treatment for CD during the study
• Any live or attenuated vaccines ≤ 4 weeks prior to randomization
• Use of IV steroids during screening, with the exception of a single IV steroid dose administered in the Emergency Department
• Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil ≤ 4 weeks prior to randomization
• Chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs). Prophylactic aspirin use up to 325 mg/day is permitted, as is occasional use of NSAIDs for conditions such as headache, arthritis, mylagia, and menstrual cramps.
• If receiving oral CSs, patients will be excluded unless the dose is stable at ≤ 20mg/day prednisone or equivalent for ≥ 2 weeks immediately prior to randomization.
• If receiving ongoing treatment with oral or 5-ASA, patients will be excluded if the dose is not stable for ≥2 weeks immediately prior to randomization.
• If receiving ongoing treatment with probiotics (e.g., Culturelle, Saccharomyces boulardii) or over-the-counter supplements (e.g., N-acetyl glucosamine, curcumin), patients will be excluded if the dose is not stable for ≥ 2 weeks immediately prior to randomization.
• If receiving ongoing treatment with ISs (e.g., 6-MP, AZA, or MTX), patients will be excluded if the dose is not stable for ≥ 8 weeks immediately prior to randomization.
• If receiving ongoing treatment with antibiotics for the treatment of CD, patients will be excluded if the dose is not stable for ≥ 2 weeks immediately prior to randomization.
Patients may continue to receive ongoing treatment with anti-diarrheals (e.g., loperamide or diphenoxylate with atropine), preferably achieving a stable dose for ≥ 2 weeks prior to randomization. However, if the patient and/or the treating physician decides to change the dose or course of anti-diarrheals at any time during screening, these patients will be allowed to participate in study.
 
Exclusion Criteria Related to Infection Risk
• Congenital or acquired immune deficiency
• Patients must undergo screening for HIV and test negative for preliminary and confirmatory tests
• Positive hepatitis C virus (HCV) antibody test result, unless the patient (1) has undetectable HCV RNA levels for > 6 months after completing a successful course of HCV antiviral treatment and an undetectable HCV RNA at screening or (2) has a known history of HCV antibody positivity with history of undetectable HCV RNA and undetectable HCV RNA at screening in the absence of history of HCV anti-viral treatment
• In the screening hepatitis B assessment (which consists of testing for hepatitis B surface antigen [HBsAg], hepatitis B core anti-body [HBcAb], and if required, hepatitis B virus [HBV] DNA), patients who test positive for HBsAg are excluded from the study. Patients who test positive for HBcAb but negative for HBsAg must have a confirmed negative HBV DNA test result to be eligible for the study and will be required to undergo periodic monitoring for HBV DNA during the study.
• Positive stool test result for ova or parasites or positive stool culture for pathogens at time of screening
• Evidence of infection with and/or treatment for Clostridium difficile or other intestinal pathogen treatment within 8 weeks prior to randomization.
• A history of active or latent TB confirmed by one of the following screening tests:
Positive tuberculin (purified protein derivative-PPD) skin test
Or,
Positive QuantiFERONTB Gold test
Subjects with a documented history of BCG vaccination must have a negative QuantiFERON test result and negative chest radiograph (see below) to be eligible.
• Suspicion of active TB on chest radiograph (X-ray, posteroanterior and lateral) taken within 3 months of randomization.
• History of recurrent opportunistic infections and/or history of severe or disseminated viral infections
• Any serious opportunistic infections that occurred ≤ 6 months prior to screening
• Any current or recent signs or symptoms (≤8 weeks before screening) of infection, except for the following:
Minor infections (e.g., common cold) that have, in the investigator’s judgment, completely resolved prior to randomization
Fungal infections of the nail beds
Oral or vaginal candidiasis that has resolved with or without treatment prior to randomization
• Any major episode of infection requiring treatment with IV antibiotics ≤ 8 weeks prior to screening or oral antibiotics ≤ 4 weeks prior to screening. Treatment with antibiotics as adjunctive therapy for CD in the absence of documented infection is not exclusionary.
 
Exclusion Criteria Related to General Safety
• Pregnancy or lactation
• Lack of peripheral venous access
• Hospitalization (other than for elective reasons) within 4 weeks prior to randomization
• Inability to comply with study protocol, in the opinion of the investigator
• Significant uncontrolled comorbidity such as neurological, cardiac (e.g., moderate to severe heart failure New York Heart Association Class III/IV), pulmonary, renal, hepatic, endocrine, or GI disorders (other than CD)
• Neurological conditions or diseases that may interfere with monitoring for PML
• Clinically significant abnormalities on screening neurologic examination
• History of demyelinating disease
• History of major neurological disorders, including stroke, MS, brain tumor, neurodegenerative disease, or poorly controlled epilepsy
• History of alcohol, drug, or chemical abuse ≤ 6 months prior to screening
• Conditions other than CD that could require treatment with > 20 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
Non-serious basal cell or squamous cell carcinoma of the skin that has been excised and is considered cured is not exclusionary.
A history of chronic myelogenous leukemia, hairy cell leukemia, melanoma, renal cell carcinoma, or Kaposi sarcoma is exclusionary irrespective of the duration of time before screening.
• History of cervical smear result at any time that indicated the presence of adenocarcinoma in situ (AIS), high-grade squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia (CIN) of Grade >1
• History of organ transplant, or cell transplantation
• Presence of metal in the body that could a pose hazard during any potential scanning in patients for whom a magnetic resonance imaging (MRI) scan is considered unsafe
Exclusion Criteria Related to Laboratory Values (at Screening)
• Serum creatinine > 2 times the upper limit of normal (ULN)
• Impaired hepatic function defined by one of the following:
Serum transaminases >3 ×ULN
Alkaline phosphatase > 3×ULN
Total bilirubin > 2.5×ULN (excluding inherited deficiencies such as Gilbert’s disease)
• Platelet count < 100,000/μL
• Hemoglobin < 8 g/dL
• Absolute neutrophil count < 1500/μL
• Absolute lymphocyte count < 500/μL