M14-033

Principal Investigator: John  Valentine
Keywords: Ulcerative Colitis , Humira Department: Gastroenterology
IRB Number: 00073210 Co Investigator:  
Specialty: Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis
Recruitment Status: Recruiting

Contact Information

Julie Will
julie.will@hsc.utah.edu
801-587-9060

Brief Summary

Objective: The primary objective is to evaluate safety and efficacy of higher induction and maintenance
dosing regimens in subjects with moderately to severely active Ulcerative Colitis (UC).

Inclusion Criteria

1. Subject must be able and willing to provide written informed consent and comply with the requirements of this study protocol.
2. Male or female ≥ 18 and ≤ 75 years of age at the Baseline visit.
3. Subject with a diagnosis of Ulcerative Colitis for 90 days or greater prior to Baseline, confirmed by endoscopy with biopsy during the Screening Period with exclusion of current infection, dysplasia and/or malignancy.
4. Active UC with a Mayo Score of 6 to 12 points and endoscopy subscore of 2 to
3 (confirmed by central reader) despite concurrent or prior treatment with a full and adequate course, in the opinion of the Investigator, of at least one of the following (oral corticosteroids or immunosuppressants as defined below):
● Subject taking oral corticosteroids, excluding budesonide or beclomethatsone:
○ Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
● For subject with a dose > 10 and ≤ 40 mg/day, dose has been stable for at least 7 days prior to Baseline and the duration of the current steroid course has been at least 14 days prior to Baseline.
● For subject with a dose ≤ 10 mg/day, dose has been stable for at least 10 days prior to Baseline and the duration of the current steroid course has been at least 14 days prior to Baseline.
● Subject taking oral budesonide:
○ Dose must not exceed 9 mg/day;
● For subject with a dose ≥ 6 mg/day, dose has been stable for at least
7 days prior to Baseline and the duration of the current steroid course has been at least 14 days prior to Baseline.
● For subject with a dose < 6 mg/day, dose has been stable for at least 10 days prior to Baseline and the duration of the current steroid course has been at least 14 days prior to Baseline.
or,
● Subject taking oral beclomethasone:
○ Dose must not exceed 5 mg/day;
Dose has been stable for at least 7 days prior to Baseline and the duration of the current steroid course has been at least 14 days prior to Baseline.
or,
 
● At least a consecutive 42-day course of azathioprine, 6-MP or MTX prior to Baseline, with a stable dose for at least 28 days prior to Baseline of azathioprine ≥ 1.5 mg/kg/day or 6-MP ≥ 1 mg/kg/day (rounded to the nearest available tablet or half tablet formulation) or a documented 6-TGN level of at least 230 pmol/8 x 108 RBC to clarify a therapeutic level was achieved on the current dosing regimen  or MTX ≥ 15 mg/week (subcutaneous [SC]/IM), or a dose that is the highest tolerated by the subject (e.g., due to leukopenia, elevated liver enzymes, nausea) during that time.
Note: If a subject is taking a drug from each of the above drug classes (oral corticosteroid and immunosuppressants) both of the drugs need to meet the above criteria.
or,
● Concurrent therapy with oral corticosteroids, or immunosuppressants (azathioprine, 6-MP or MTX) is not required for subjects not currently taking these medications who were previously treated during the past 1 year and have confirmed documentation of failure to respond, or were previously treated
during the past 5 years and have confirmed documentation indicating lack of tolerability, see Section 10.1.
5. Subject may be included if they have previously experienced a benefit from infliximab and discontinued its use due to a subsequent loss of response (i.e., judged by the Investigator to have responded to infliximab in the past and subsequently experienced an overall lack of improvement or worsening of UC
related symptoms) or intolerance (i.e., in the opinion of the investigator therapy was discontinued as a result of a significant acute or delayed reaction to the medication). Confirmed documentation indicating loss or response or lack of tolerability will be required, see Section 10.1 and Appendix H.
6. If female, subject is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy and/or hysterectomy) or is of childbearing potential and is practicing an approved method of birth control throughout the study and for 150 days after last dose of study drug. Examples of approved methods of birth control which
result in a low failure rate (i.e., less than 1% per year) when used consistently and correctly are (see local informed consent for more detail):
● Implants, injectables, some intrauterine devices (IUDs), intrauterine hormonereleasing system (IUS);
● Sexual Abstinence (when in line with preferred and usual lifestyle of the subject);
● A vasectomized partner;
● Hormonal contraceptives for at least 90 days prior to study drug administration .
Note: low-dose progestin-only oral contraceptives such as norethindrone 0.35 mg and lynestenol 0.5 mg are not considered adequate.
7. If female, subject is not breast-feeding throughout the study and for 150 days after last dose.
8. Subject has a negative TB Screening Assessment. If the subject has evidence of a latent TB infection, the subject must initiate and complete a minimum of 2 weeks (or per local guidelines, whichever is longer) of an ongoing TB prophylaxis or have documented completion of a full course of TB prophylaxis, prior to Baseline (see Section 5.3.1.1).
9. Subject is judged to be in otherwise good health as determined by the Principal Investigator based upon the results of medical history, laboratory profile, physical examination, chest x-ray, and a 12-lead ECG performed during Screening.
10. Subject must be able and willing to self-administer SC injections or have a qualified person available to administer SC injections.

 

Exclusion Criteria

1. Subject with diagnosis and/or history of Crohn's disease (CD) or diagnosis of indeterminate colitis (IC).
2. Current diagnosis of fulminant colitis and/or toxic megacolon.
3. Subject with disease limited to the rectum (ulcerative proctitis) during the screening endoscopy.
4. Received therapeutic enema or suppository, other than required for endoscopy, within 7 days prior to the Screening endoscopy and during the remainder of the Screening Period.
5. History of subtotal colectomy with ileorectostomy or colectomy with ileoanal pouch, Kock pouch, or ileostomy or is planning bowel surgery.
6. Received cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to Baseline.
7. Positive pregnancy test at Screening or (serum) Baseline (urine).
8. Female who is breast-feeding or considering becoming pregnant during the study.
9. History of clinically significant drug or alcohol abuse in the last 12 months.
10. Subject on azathioprine, 6-MP, or MTX who:
● Has not been on these medications for at least 42 days prior to Baseline; or
● Has not been on stable doses of these medications for at least 28 days prior to Baseline; or
● Has discontinued these medications within 14 days of Baseline.
11. Subject on oral aminosalicylates who:
● Has not been on stable doses of these medications for at least 14 days prior to Baseline; or
● Has discontinued use of aminosalicylates within 14 days of Baseline.
12. Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subject on oral budesonide > 9 mg/day; or subject on oral beclomethasone >5 mg/day; or
● Subject taking an oral corticosteroid (excluding budesonide):
○ dose > 10 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
○ dose > 10 mg/day, but has not been on a current steroid course of at least 14 days in duration prior to Baseline; or
○ dose ≤ 10 mg/day or equivalent, but has not been on a stable dose for at least 10 days prior to Baseline; or
○ dose ≤ 10 mg/day or equivalent but has not been on a current steroid course of at least 14 days in duration prior to Baseline, or
● Subject taking oral budesonide:
○ dose ≥ 6 mg/day, but has not been on a stable dose for at least 7 days prior to Baseline; or
○ dose ≥ 6 mg/day, but has not been on a current steroid course of at least 14 days in duration prior to Baseline; or
○ dose < 6 mg/day dose but has not been on a stable dose of at least 10 days prior to Baseline; or
○ dose < 6 mg/day but has not been a current steroid course of at least 14 days in duration prior to Baseline;
● Subject taking oral beclomethasone:
○ has not been on a stable dose for at least 7 days prior to Baseline; or
○ has not been on a current steroid course of at least 14 days in duration prior to Baseline. 
or Has been taking, both oral budesonide (or oral beclomethasone) and oral prednisone (or equivalent)
simultaneously. 
and/or
Has discontinued use of corticosteroids within 14 days of Baseline.
13. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
14. Positive Clostridium difficile (C. difficile) toxin stool assay during the Screening Period.
15. Currently receiving total parenteral nutrition (TPN).
16. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to Week 0 (Baseline), whichever is longer.
17. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives within 14 days prior to the Baseline Visit.
18. Subject who has previously used infliximab:
● and has not clinically responded at any time ("primary non-responder") unless subject experienced a treatment limiting reaction;
or,
● who used infliximab within 56 days of Baseline.
19. Prior exposure to medications that have a potential or known association with progressive multifocal leukoencephalopothy (PML), includind participation in a clinical trial of investigational agents targeting white cell trafficking (i.e., natalizumab [Tysabri ®], rituximab [Rituxan®], efalizumab [Raptiva®]) or previous participation in an adalimumab clinical study. Prior exposure to any anti-TNF agent other than
infliximab (including etanercept [Enbrel®], golimumab [Simponi®] or certolizumab pegol [Cimzia®]). Prior exposure to ustekinumab (Stelara®), tofacitinib (Xeljanz®) or vedolizumab.
20. Subject with known hypersensitivity to the excipients of adalimumab as stated in the prescribing information.
21. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of demyelinating disease.
22. Current evidence of dysplasia or history of malignancy (including lymphoma and leukemia) other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma or localized carcinoma in situ of the cervix. If the Screening endoscopy shows evidence of current dysplasia or malignancy, subject may not be enrolled in the study.
23. History of invasive infection (e.g., listeriosis and histoplasmosis), human immunodeficiency virus (HIV).
24. Subject with any active viral infection that based on the investigator's clinical assessment makes the subject an unsuitable candidate for the study.
25. Subjects with a positive result for the Hepatitis B surface antigen (HBs Ag) will be excluded. Samples that are negative for HBs Ag will be tested for surface antibodies (HBs Ab) and core antibodies (HBc Ab Total). Subjects with HBs Ag (–), HBs Ab (–), and HBc Ab Total (+) require PCR qualitative testing for HBV DNA. Any HBV DNA PCR result that meets or exceeds detection sensitivity will be exclusionary. Subjects with a negative HBs Ag test and tests showing the results below do not require HBV DNA

PCR qualitative testing:

HBc Ab Total (–) and HBs Ab* (–)

HBc Ab Total (–) and HBs Ab* (+)

HBc Ab Total (+) and HBs Ab* (+)

●*For HBs Ab test results, a (-) result is equivalent to nonreactive and a (+) result is equivalent to reactive.

26. Chronic recurring infections or active TB.
27. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident and/or any other condition which would put the subject at risk by participation in the study.
28. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
29. Screening laboratory and other analyses show any of the following abnormal results:
● AST, ALT > 1.75 × upper limit of the reference range;
● WBC count < 3.0 × 109/L;
● Electrocardiogram (ECG) – with clinically significant abnormalities;
● Total bilirubin ≥ 3 mg/dL; except for subjects with isolated elevation of indirect bilirubin relating to Gilbert syndrome;
 Serum creatinine > 1.6 mg/dL.