Celgene 0301-UC-002

Principal Investigator: John  Valentine
Keywords: Ulcerative Colitis , SMAD 7 Department: Gastroenterology
IRB Number: 00087612 Co Investigator:  
Specialty: Gastroenterology
Sub Specialties: Inflammatory Bowel Disease/Crohn's/Ulcerative Colitis
Recruitment Status: Recruiting

Contact Information

Heather Munk

Brief Summary

Primary Objective
-To explore the effect of GED-0301 on clinical activity, as measured by the modified Mayo score (MMS), in subjects with active UC.
Secondary Objectives
-To explore the effect of GED-0301 on endoscopic outcome, as measured by the Mayo endoscopic subscore, in subjects with active UC.
-To evaluate the safety and tolerability of GED-0301 in subjects with active UC.
Exploratory Objectives
-To evaluate the change in biomarkers such as hsCRP and FCP in response to GED-0301 in subjects
with active UC.
-To explore the effects of GED-0301 on histological scores in intestinal mucosal biopsies from subjects with active UC.
-To explore the PD effects of GED-0301 on gene expression in the intestinal mucosal in subjects with
active UC.
-To explore the association of the PD parameters with the efficacy of GED-0301 in subjects with active UC.
-To measure the systemic exposure of GED-0301 in subjects with active UC.
1.3.1. Study Rationale and Purpose
This study represents the first investigation of GED-0301 in subjects with active UC. GED-0301
has already demonstrated to be effective and safe in subjects with CD. In vitro and in vivo studies have demonstrated that TGF-β1 acts as a potent negative regulator of mucosal inflammation and the inhibition of its activity results in the development of colitis, which shows
Confidential and Proprietary 21 Protocol GED-0301-UC-002 Final: 25 Aug 2015 immunomorphological similarities with CD or UC (Powrie, 1996; Neurath, 1996). GED-0301 inhibits the expression of Smad7, a key regulatory modulator of TGF-β1, restoring TGF-β1 functionality. Additionally, animal models of colitis that resemble UC (oxazolone-induced colitis models) have shown that mice treated with GED-0301 exhibited less weight loss, less mortality and markedly decreased gastrointestinal (GI) inflammation, as noted histologically.
The purpose of this study is to: 1) explore the effectiveness and evaluate the safety of GED-0301
in the treatment of subjects with active UC; and 2) evaluate the extent of the effect in the colon
with the current formulation of GED-0301.

Inclusion Criteria

4.2. Inclusion Criteria
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is ≥ 18 years of age at the time of signing the ICF.
2. Subject is able to understand and voluntarily sign an ICF prior to conducting any studyrelated
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Subject must have a diagnosis of UC with a duration of at least 3 months prior to screening.
5. Subject must have moderate to severe UC, defined as MMS ≥ 4 to ≤ 9 at screening.
6. Subject must have a Mayo endoscopic subscore ≥ 2 at screening.
7. Subject must have failed or experienced intolerance to at least one of the following:  aminosalicylates; budesonide; systemic corticosteroids; immunosuppressants (eg, 6-mercaptopurine [6-MP], azathioprine [AZA], or methotrexate [MTX]) or TNF-α blockers (eg, infliximab, adalimumab, or golimumab) (See Appendix E).
8. Subject must meet the following laboratory criteria:
   a. White blood cell count ≥ 3000/mm3 (≥ 3.0 X 109/L)
   b. Platelet count ≥ 100,000/mm3 (≥ 100 X 109/L)
   c. Serum creatinine ≤ 1.5 mg/dL (≤ 132.6 μmol/L)
   d. Aspartate transaminase (AST/serum glutamic oxaloacetic transaminase [SGOT]) and alanine            transaminase (ALT/serum pyruvic transaminase [SGPT])  2.5 X upper limit of normal (ULN)
   e. Total bilirubin ≤ 2 mg/dL (≤ 34 μmol/L) unless there is a confirmed diagnosis of Gilbert's               disease
   f. Hemoglobin ≥ 9 g/dL (≥ 5.6 mmol/L)
   g. Activated partial thromboplastin time (APTT)  1.5 X ULN
9. Females of childbearing potential (FCBP1) must have a negative pregnancy test at the Screening and Baseline Visits. While on IP and for at least 28 days after taking the last dose of IP, FCBP who engage in activity in which conception is possible must use one of the approved contraceptive options described below:
   Option 1: Any one of the following highly effective methods: hormonal
                contraception (oral, injection, implant, transdermal patch, vaginal ring); intrauterine
                device (IUD); tubal ligation; or partner’s vasectomy;
   Option 2: Male or female condom PLUS 1 additional barrier method: (a) diaphragm with                               spermicide; (b) cervical cap with spermicide; or (c) contraceptive sponge with
10. Male subjects (including those who have had a vasectomy) when engaging in sexual activity with females who are able to become pregnant must use barrier contraception (male latex condom or nonlatex condom NOT made out of natural [animal] membrane [for example, polyurethane]) while on IP and for at least 28 days after the last dose.

Exclusion Criteria

4.3. Exclusion Criteria
The presence of any of the following will exclude a subject from enrollment:
1. Subject has a diagnosis of CD, indeterminate colitis, ischemic colitis, microscopic colitis, radiation colitis or diverticular disease-associated colitis.
2. Subject has ulcerative colitis restricted to distal 15 cm or less (eg, ulcerative proctitis).
3. Subject had surgery as a treatment for UC or who, in the opinion of the Investigator, is likely to require surgery for UC during the study.
4. Subject has clinical signs suggestive of fulminant colitis or toxic megacolon.
5. Subject is stool positive for any enteric pathogen or Clostridium difficile (C. difficile) toxin at screening.
6. Subject has history of colorectal cancer or colorectal dysplasia.
7. Prior treatment with more than 2 TNF-α blockers (eg, infliximab, adalimumab, or golimumab).
8. Prior treatment with any integrin antagonists (eg, natalizumab or vedolizumab).
9. Use of TNF-α blockers within 8 weeks of the screening.
10. Subject had prior treatment with mycophenolic acid, tacrolimus, sirolimus, cyclosporine,  thalidomide or apheresis (eg, Adacolumn®) for the treatment of UC. In addition, prior use of any of these treatment modalities for an indication other than UC within 8 weeks of screening is also excluded.
11. Subject has received intravenous (IV) corticosteroids within 2 weeks of screening. 
12. Subject has received topical treatment with 5-ASA or corticosteroid enemas or suppositories within 2 weeks of screening.
13. Subject has received total parenteral nutrition (TPN) within 4 weeks of screening.
14. Subject has a history of any clinically significant neurological, renal, hepatic, gastrointestinal, pulmonary, metabolic, cardiovascular, psychiatric, endocrine, hematological disorder or disease, or any other medical condition that, in the investigator's opinion, would prevent the subject from participation in the study.
15. Subject has any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she was to participate in the study or confounds the ability to interpret data from the study.
16. Subject is pregnant or breastfeeding.
17. Subject has a history of any of the following cardiac conditions within 6 months of screening: myocardial infarction, acute coronary syndrome, unstable angina, new onset atrial fibrillation, new onset atrial flutter, second- or third-degree atrioventricular block, ventricular fibrillation, ventricular tachycardia, heart failure, cardiac surgery, interventional cardiac catheterization (with or without a stent placement), interventional electrophysiology procedure, or presence of implanted defibrillator.
18. Subject has a known active current or history of medically important recurrent bacterial, viral, fungal, mycobacterial or other infections (including but not limited to tuberculosis and atypical mycobacterial disease and Herpes zoster), human immunodeficiency virus (HIV), or any major episode of infection requiring hospitalization or treatment with IV or oral antibiotics within 4 weeks of screening.
19. Subject has a history of congenital or acquired immunodeficiency (eg, common variable immunodeficiency disease).
20. Subject has a history of malignancy, except for:
   a. Treated (ie, cured) basal cell or squamous cell in situ skin carcinomas
   b. Treated (ie, cured) cervical intraepithelial neoplasia or carcinoma in situ of the cervix with no          evidence of recurrence within the previous 5 years
21. Subject has received investigational drug or device within 1 month of screening.
22. Subject has a history of alcohol, drug, or chemical abuse within the 6 months prior to screening.
23. Subject has a known hypersensitivity to oligonucleotides or any ingredient in the IP.
24. Subject has prior treatment with GED-0301 or participated in a clinical study involving GED-0301.