M14-115

Principal Investigator: John  Valentine
Keywords: Crohns Department: Gastroenterology
IRB Number: 00073136 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

Objectives

The primary objective of this study is to assess the efficacy and safety of two adalimumab induction
regimens in achieving clinical remission defined as Crohn's Disease Activity Index (CDAI) < 150 at
Week 4 and endoscopic improvement defined as Simplified Endoscopic Score for Crohn's Disease
(SES-CD) ≤ 4 and at least a 2 point reduction versus baseline and no subscore greater than 1 in any
individual variable at Week 12 in subjects with moderately to severely active Crohn's disease and
evidence of mucosal ulceration at Baseline.
 
Additional Objectives:
 To assess the safety and efficacy of two adalimumab induction regimens in reducing signs and
symptoms of Crohn's disease at Week 12.
 To assess pharmacokinetics (PK) and immunogenicity of two adalimumab induction regimens
following subcutaneous (SC) administration.
 
Additional Objectives:
 To assess the safety and efficacy of two adalimumab induction regimens in reducing signs and
symptoms of Crohn's disease at Week 12.
 To assess pharmacokinetics (PK) and immunogenicity of two adalimumab induction regimens
following subcutaneous (SC) administration.

Inclusion Criteria

1. Males and females ≥ 18 and ≤ 75 years of age at Baseline.
2. Diagnosis of colonic, ileocolonic, or ileal Crohn's disease for ≥ 3 months prior to Baseline and confirmed by endoscopy during the Screening period or endoscopy performed within 45 days of Baselinewith exclusion of current infection, dysplasia, and/or malignancy. Appropriate documentation of biopsy results consistent with the diagnosis of CD, in the assessment of the Investigator, must be available.
3. Simplified Endoscopic Score for Crohn's Disease (SES-CD) ≥ 6, excluding the presence of narrowing component, on screening endoscopy (or SES-CD ≥ 4,excluding the presence of narrowing component, for patients with disease limited to the ileum),, on screening endoscopy or endoscopy performed within 45 days before Baseline, confirmed by a central reader.
4. Crohn's Disease Activity Index (CDAI) ≥ 220 and ≤ 450 at Baseline 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 and/or immunosuppressants or both as defined below):
● Subject taking oral corticosteroids, excluding budesonide:
○ Oral corticosteroid dose must be ≤ 40 mg/day (prednisone or equivalent);
● For subjects 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 subjects 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 subjects 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 subjects 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,
● At least a consecutive 42-day course of azathioprine, 6-MP, or injectable 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 documented 6-TGN level of at least 230  pmol/8 × 108 RBC to clarify a theraputic level was achieved on the current dosing regimen) or MTX ≥ 15 mg/week (subcutaneous [SC]/Intramuscular [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 both an oral corticosteroid and an immunosuppressant listed above, BOTH of the drugs need to meet the above criteria. Oral MTX use is allowed during the study (at a stable dose for 28 days prior to Baseline) however current or prior use of oral MTX is not sufficient for inclusion into the study.
or
● Concurrent therapy with oral corticosteroids or immunosuppressants (azathioprine, 6-MP or SC/IM 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 (judged by the Investigator to have responded to infliximab in the past and subsequently experienced an overall lack of improvement or worsening of CD-related symptoms) or intolerance (in the opinion of the Investigator therapy was discontinued as a result of a significant acute or delayed infusion/administration reaction to the medication) to the agent. Confirmed documentation indicating loss of response or lack of tolerability will be required.
6. Subject has a negative TB Screening Assessment (including a PPD test or QuantiFERON TB Gold test [or equivalent]) and negative chest x-ray (CXR – PA and lateral view) at Screening. If the subject has evidence of a latent TB infection; the subject must initiate and complete a minimum of 2 weeks of an ongoing TB prophylaxis or have documented completion of a full course of anti TB prophylaxis, prior to Baseline.
7. 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 are (see local informed consent for more detail):
● Implants, injectables, some intrauterine devices (IUDs), intrauterine hormone releasing system (IUS)
● Sexual abstinence (when in line with preferred and usual lifestyle of the subject)
● 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.
8. Subject must be able and willing to give written informed consent and to comply with the requirements of this study protocol.
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, CXR, and a 12-lead electrocardiogram (ECG) performed during Screening.
10. Subject must be able and willing to self-administer subcutaneous (SC) injections or have a qualified person available to administer SC injections.
 
Criteria Rationale
(1)In accordance with good clinical practice (GCP)
(2 – 9) In order to select the appropriate subject population with a disease status representative of the target population for evaluation.
(10) In order to select subjects who will comply with study procedures for adequate evaluation.

 

Exclusion Criteria

1. Subject with a current diagnosis of ulcerative colitis or indeterminate colitis.
2. Subject on azathioprine, 6-mercaptopurine (6-MP), methotrexate (MTX), or another immunosuppressant (e.g., thalidomide) 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.
3. Subject on oral aminosalicylates who:
● Has not been on stable doses of these medications for at least 28 days prior to Baseline; or
● Has discontinued use of aminosalicylates within 14 days of Baseline.
4. Subject on oral corticosteroid > 40 mg/day (prednisone or equivalent) or subjects on budesonide > 9 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 for at least 14 days 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 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 for at least 14 days 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 the current course has not been at least 14 days in duration prior to Baseline; or
Has been taking both oral budesonide and prednisone (or equivalent) simultaneously, with the exception of inhalers.
5. Received intravenous corticosteroids within 14 days prior to Screening or during the Screening Period.
6. Subject who has had surgical bowel resections within the past 6 months or is planning any resection at any time point while enrolled in the study.
7. Subject with a symptomatic bowel stricture.
8. Subject with an abdominal or peri-anal abscess.
9. Subject with an ostomy or ileoanal pouch.
10. Subject who has short bowel syndrome.
11. Subject has received therapeutic enema or suppository, other than required for endoscopy, within 14 days prior to Screening and/or during the Screening period.
12. Prior exposure to medications that have a potential or known association with progressive multifocal leukoencephalopathy (PML), including participation in a clinical trial of investigational agents targeting white cell trafficking (eg., natalizumab [Tysabri®], rituximab [Rituxan®], efalizumab [Raptiva®]. 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 (Entyvio®).
13. Subject who received any investigational agent or procedure within 30 days or 5 half-lives prior to the Baseline, whichever is longer.
14. Subject who previously received treated with adalimumab or previously participated in an adalimumab clinical study.
15. Subject received cyclosporine, tacrolimus, or mycophenolate mofetil within 60 days prior to Baseline.
16. Subject who previously received stem cell transplantation.
17. Subject who previously received fecal microbial transplantation.
18. Subject that received non-steroidal anti-inflammatory drugs (NSAIDs) within 14 days prior to Screening and during the Screening visit, Visit, except low-dose aspirin for prevention of heart attacks,unstable angina or transient ischemic attacks or topical NSAIDs.
19. Infection(s) requiring treatment with intravenous (IV) anti-infectives within 30 days prior to the Baseline Visit or oral anti-infectives for non-Crohn's disease related infections within 14 days prior to the Baseline Visit.
20. Subjects on Crohn's disease related antibiotics that have not been on stable doses for at least 4 weeks prior to Baseline. Subjects on Crohn's disease related antibiotics that have discontinued these medications within 4 weeks of Baseline are excluded.
21. Subject currently receiving total parenteral nutrition (TPN) or plan to receive TPN at any time during the course of the study.
22. Subject with positive Clostridium difficile (C. difficile) toxin stool assay during the Screening period.
23. 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.
24. Known hypersensitivity to adalimumab or its excipients.
25. 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.
26. History of demyelinating disease (including myelitis) or neurologic symptoms suggestive of demyelinating disease.
27. History of invasive infection (e.g., listeriosis and histoplasmosis) or human immunodeficiency syndrome (HIV).
28. Subject with an active systemic viral infection or any active viral infection that based on the investigator's clinical assessment makes the subject an unsuitable candidate for the study.
29. 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.

30. Chronic recurring infections.
31. Subject with active TB.
32. Subject with latent TB infection unless there is evidence the subject initiated and completed a minimum of 2 weeks of an ongoing TB prophylaxis or has documented completion of a full course of anti-TB prophylaxis, prior to Baseline.
33. History of moderate to severe congestive heart failure (NYHA class III or IV), recent cerebrovascular accident and any other condition which, in the opinion of the Investigator, would put the subject at risk by participation in the study.
34. Subject with a previous history of dysplasia of the gastrointestinal tract, or found to have dysplasia in any biopsy performed during the Screening endoscopy or endoscopy performed within 45 days before Baseline.
35. Positive pregnancy test at Screening (serum) or Baseline (urine).
36. Female subjects who are breastfeeding or considering becoming pregnant during the study.
37. History of clinically significant drug or alcohol abuse in the last 12 months.
38. Clinically significant abnormal screening laboratory results as evaluated by the Investigator.
39. 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.
40. Subject is considered by the Investigator, for any reason, to be an unsuitable candidate for the study.
 
Criteria Rationale
(1) To avoid medical conditions that may compromise the ability to identify subjects with the correct diagnosis or to interpret medical importance of clinical results.
(2 – 5) To exclude subjects who have not been treated with conventional therapies.
(19 – 20, 22, 24 – 36, 39) To reduce the risk to subjects or others and/or to exclude underlying conditions that would compromise the subject's safety.
(40) To maintain the integrity of other aspects of study conduct, including, subject sampling, treatment procedures, etc.
(6 – 10, 11 – 18, 21, 23) To avoid bias for the evaluation of efficacy and safety by concomitant use of other medications or treatments.
(37, 38) To exclude subjects who maybe at increased risk for protocol non-adherence or premature discontinuation.