GA28950

Principal Investigator: John  Valentine
Keywords: Ulcerative Colitis , Etrolizumab Department: Gastroenterology
IRB Number: 00081262 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

The primary efficacy objectives for this study are as follows:

  • To evaluate the efficacy of etrolizumab (105 mg subcutaneous [SC] every 4 weeks [Q4W]) compared with placebo for the induction of remission in patients with ulcerative colitis (UC) as determined by the Mayo Clinic Score (MCS) at Week 14
  • To evaluate the efficacy of etrolizumab (105 mg SC Q4W) compared with placebo for maintenance of remission at Week 66 for randomized patients in remission at Week 14


The safety objectives for this study are as follows:

  • To evaluate the overall safety and tolerability of etrolizumab compared with placebo during induction and maintenance therapy over a period of 66 weeks
  • To evaluate the incidence and severity of infection-related adverse events
  • To evaluate the incidence of malignancies
  • To evaluate the incidence and severity of hypersensitivity reactions
  • To evaluate the incidence and the clinical significance of anti-therapeutic antibodies (ATAs)


The PK objectives for this study are as follows:

  • To evaluate etrolizumab serum concentration at the time of primary endpoint evaluation (Weeks 14 and 66) and at predose time in the steady state during the maintenance dosing period
  • To evaluate the inter-individual variability and potential covariate effects on etrolizumab serum exposure


The exploratory pharmacodynamics (PD) and diagnostic objectives for this study are as follows:

  • To evaluate the relationship between baseline colonic mucosal biomarkers and/or peripheral blood and response to study drug, including but not limited to the αE integrin
  • To evaluate the levels of biomarkers in colonic tissue and/or peripheral blood during the treatment period, including but not limited to the αE integrin.
  • To evaluate the PD effects on biomarkers in colonic tissue and/or peripheral blood following study drug

 

Inclusion Criteria

• Able and willing to provide written informed consent
• 18−80 years of age, inclusive
• Diagnosis of UC established at least 6 months prior to Day 1 by clinical and
endoscopic evidence. This diagnosis should be corroborated by histopathology
conducted at any time prior to screening and documented by a histopathology report
(Note: histopathology may be performed at screening, if no prior report is readily
available).
• Moderately to severely active UC as determined by an MCS of 6−12 with an
endoscopic subscore ≥ 2 as determined by the central reading procedure described
in Section 4.6.1.4, a rectal bleeding subscore ≥ 1, and a stool frequency subscore of
≥ 1 within 14 days of Day 1. See Section 4.6.2.1 for additional information
regarding the time window.
• Evidence of UC extending a minimum of 20 cm from the anal verge as determined
by baseline endoscopy (flexible sigmoidoscopy or colonoscopy) performed
between 4 and 10 days prior to Day 1. See Section 4.6.2.1 for additional
information regarding the time window.
• Washout of anti-TNF therapy for at least 8 weeks preceding Day 1
• Intolerant or refractory to one or two of the following TNF-inhibitors within the
previous 5 years as defined below:
Signs and symptoms of persistently active disease despite a history of at least
one induction regimen of the following agents:
Infliximab: 5 mg/kg IV, 2 doses
Adalimumab: 160 mg SC followed by 80-mg dose
Golimumab: 200 mg SC followed by a 100-mg dose
OR
Recurrence of symptoms during scheduled maintenance dosing following prior
clinical benefit (discontinuation despite clinical benefit does not qualify)
OR
History (within previous 5 years) of intolerance of one or two TNF-inhibitors
(including but not limited to infusion-related reaction, congestive heart failure,
infection)
• Any ongoing UC therapy must be at stable doses:
May be receiving oral 5-ASA compounds provided that the dose has been
stable for ≥ 4 weeks immediately prior to Day 1
May be receiving oral corticosteroid therapy (prednisone at a stable dose
of ≤ 30 mg a day, or equivalent steroid) provided that the dose has been stable
for at least 4 weeks immediately prior to enrollment if corticosteroids have just
been initiated or for the 2 weeks immediately prior to Day 1 if corticosteroids are
being tapered
May be receiving budesonide MMX therapy at a stable dose of up to 9 mg
a day for ≥ 4 weeks prior to Day 1
May be receiving probiotics (e.g., Culturelle, Saccharomyces boulardii),
provided that the dose has been stable for at least 2 weeks immediately prior to Day 1
May be receiving AZA, 6-MP, or MTX provided that the dose has been stable
for at least 8 weeks immediately prior to Day 1
• For women who are not postmenopausal (at least 12 months of
non−therapy-induced amenorrhea) or surgically sterile (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).
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and 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 (refrain from heterosexual intercourse) or
use contraceptive measures, a condom, and agreement to refrain from donating
sperm, as defined below:
With female partners of childbearing potential or pregnant female partners, men
must remain abstinent or use a condom during the treatment period and for at least
24 weeks after the last dose of study drug to avoid exposing the embryo to study
drug. Men must refrain from donating sperm during this same period.
The reliability of sexual abstinence should be evaluated in relation to the
duration of the clinical trial and 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.
• Must have received a colonoscopy within the past year or be willing to undergo a
colonoscopy in lieu of a flexible sigmoidoscopy at screening. This colonoscopy
must:
Confirm disease extent (defined as 1) left-sided colitis [up to the splenic
flexure], 2) extensive colitis [beyond the splenic flexure but not involving the
entire colon], and 3) pancolitis; see Section 4.6.1.4)
 
Include removal of any adenomatous polyps
Document  evidence of surveillance for dysplasia for all patients with left-sided
colitis of > 12 years’ duration and total/extensive colitis of > 8 years duration
 

Exclusion Criteria

 
Patients who meet any of the following criteria will be excluded from study entry:
 
Exclusion Criteria Related to Inflammatory Bowel Disease
 
•     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
 
Exclusion Criteria Related to Prior or Concomitant Therapy
 
•     Any prior treatment with etrolizumab or other anti-integrin agents (including natalizumab, 
vedolizumab, and efalizumab)
•    Any prior treatment with rituximab
 
•     Use of 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 (e.g., alemtuzumab or visilizumab) within 12 months 
prior to Day 1, except for AZA and 6-MP
 
•     Use of cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 4 weeks 
prior to Day 1
 
•     Chronic nonsteroidal anti-inflammatory drug (NSAID) use (Note:  occasional use of NSAIDs and 
acetaminophen [e.g., headache, arthritis, myalgias, or menstrual cramps] and aspirin up to 325 mg 
daily is permitted.)
 
•     Patients who are currently using anticoagulants including but not limited to warfarin, 
heparin, enoxaparin, dabigatran, apixaban, rivaroxaban.  (Note that antiplatelet agents such as 
aspirin up to 325 mg daily or clopidogrel are permitted.)
•     Patients who have received treatment with corticosteroid enemas/suppositories and/or topical 
(rectal) 5-ASA preparations ≤ 2 weeks prior to Day 1
•     Apheresis (i.e., Adacolumn apheresis) within 2 weeks prior to Day 1
 
•     Received any investigational treatment including investigational vaccines within 12 weeks 
prior to Day 1 of the study or 5 half-lives of the investigational product, whichever is greater
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)
 
•     Patients administered tube feeding, defined formula diets, or parenteral 
alimentation/nutrition who have not discontinued these treatments ≥ 3 weeks prior to Day 1
 
Exclusion Criteria Related to General Safety
 
•    Pregnant or lactating
 
•    Lack of peripheral venous access
 
•     Hospitalized (other than for elective reasons) within 4 weeks prior to screening and during 
screening
•     Inability to comply with study protocol, in the opinion of the investigator
 
•     Significant uncontrolled co-morbidity, such as cardiac (e.g., moderate to severe heart 
failure New York Heart Association [NYHA] Class III/IV), pulmonary, renal, hepatic, endocrine, or 
gastrointestinal disorders (excluding UC)
 
•     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 ≤ 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 with the following caveats:
 
Local basal 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 a cervical smear indicating the presence of adenocarcinoma in situ (AIS), high-grade 
squamous intraepithelial lesions (HSIL), or cervical intraepithelial neoplasia (CIN) of Grade > 1 
is exclusionary, irrespective of the duration of time before screening.
Exclusion Criteria Related to Infection Risk
 
•   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, unless the patient (1) has
undetectable HCV RNA levels for > 6 months after completing a successful course
of HCV anti-viral treatment and an undetectable HCV RNA at screening OR
(2) has a known history of HCV antibody positivity with history of undetectable
HCV RNA for > 6 months and undetectable HCV RNA at screening in the absence
of history of HCV anti-viral treatment.
 
•     Patients must undergo screening for hepatitis B virus (HBV). This includes testing for HBsAg 
(HBV surface antigen), anti-HBc total (HBV core antibody total), and HBV DNA (patients who test 
negative for these tests are eligible for this study):
Patients who test positive for surface antigen (HBsAg +) are not eligible for this study, 
regardless of the results of other hepatitis B tests.
Patients who test positive only for core antibody (anti-HBc +) must undergo further testing for 
hepatitis B DNA (HBV DNA test).
 
If the HBV DNA test result is positive, the patient is not eligible for this study.
In the event HBV DNA test cannot be performed, the patient is not eligible for this study.
If the HBV DNA test result is negative, the patient is eligible for this study. These patients will 
undergo periodic monitoring for HBV DNA during the study.
•     Evidence of or treatment for Clostridium difficile (as assessed by C. difficile toxin 
testing) within 60 days prior to Day 1 or other intestinal pathogens (as assessed by stool culture 
and ova and parasite evaluation) within 30 days prior to Day 1
•     Evidence of or treatment for clinically significant cytomegalovirus (CMV) colitis (based on 
the investigator’s judgment) within 60 days prior to Day 1.  Laboratory confirmation of CMV from 
colon biopsy is required during screening evaluation only if clinical suspicion is high and to 
determine the need for CMV treatment
•     History of active or latent TB, regardless of treatment history (see Section 4.6.1.5) 
Patients with a history of active or latent TB (based on a positive screening
assay, either purified protein derivative [PPD] skin test or QuantiFERONTB
Gold test, see below) are not eligible for this study.
 
Patients with a chest X-ray (posteroanterior [PA] and lateral) within 3 months of Day 1 suspicious 
for pulmonary TB are not eligible for this study.
•     History of recurrent opportunistic infections and/or history of severe disseminated viral 
infections (e.g., herpes)
•     Any serious opportunistic infection within the last 6 months
 
•     Any current or recent signs or symptoms (within 4 weeks before screening and during 
screening) of infection, except for the following:
 
Minor infections (e.g., common cold) that have, in the investigator’s judgment, completely resolved 
prior to Day 1
Fungal infections of the nail beds
 
Oral or vaginal candidiasis that has resolved with or without treatment prior to Day 1
 
 
•     Any major episode of infection requiring hospitalization or 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 Day 1
 
•    History of organ transplant
 
Exclusion Criteria Related to Laboratory Abnormalities (at Screening)
 
•     Serum creatinine > 2 × upper limit of normal (ULN)
 
•     ALT or AST > 3 × ULN or alkaline phosphatase > 3 × ULN or total bilirubin > 2.5 × ULN 
(unconjugated hyperbilirubinemia that is associated with known Gilbert's is not an exclusion 
criterion)
•    Platelet count < 100,000/µL
 
•    Hemoglobin < 8 g/dL
 
•   Absolute neutrophil count < 1500/µL
 
•   Absolute lymphocyte count < 500/µL