Clinical trial NCT01453491: A Phase 1b Study to Assess the Safety and Anti-inflammatory Effects of Two Different Doses of SRT2104 in Patients With Ulcerative Colitis
Official title: A Phase 1b, Exploratory Study to Assess the Safety, Tolerability, Colonic Tissue Exposure, and Anti-Inflammatory Effects of Two Different Doses of SRT2104 in Subjects With Mild to Moderate Ulcerative Colitis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colitis, Ulcerative
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: GlaxoSmithKline
First posted: 2011-10-18
Enrollment: 17
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this research study is to:

* 1) Test the safety and tolerability of 2 different oral doses of SRT2104 in subjects with ulcerative colitis
* 2) Determine the amount of SRT2104 measured from a single blood sample in addition to colon and/or rectal tissue samples (biopsies)
* 3) Determine whether SRT2104 has any anti-inflammatory effect on the colon and/or rectum when taken orally for 8 weeks
* 4) Determine whether SRT2104 causes any detectable changes to specific biomarkers. A biomarker is a biological marker (or substance such as a protein) that is used as an indicator of changes in a biological state that corresponds to the risk or progression of a disease.


Eligibility criteria: Inclusion Criteria:

* Mild to moderately active ulcerative colitis as evidenced by Mayo score 6-10 (inclusive) with rectal bleeding score ≥1, endoscopy score between 2-3 (inclusive), and physician's rating of disease activity \<3 at Day -5
* Colonic inflammation extending proximal to the rectum (i.e., greater than 15 cm in extent) on baseline sigmoidoscopy at Day -5
* Confirmed diagnosis of ulcerative colitis for at least 3 months prior to the Screening Visit (Visit 1)
* Male or female between 18 and 75 years, inclusive
* Body weight \>50 kg and BMI ≥18 kg/m\^2 at Screening (Visit 1)
* Capable of giving written informed consent, and willing and able to comply with the requirements of the protocol
* Female subjects of child-bearing potential must be willing to use reliable contraception from Visit 1 through the follow-up visit (Day 70)

Exclusion Criteria:

* Suspicion of Crohn's disease, indeterminate colitis, microscopic colitis, segmental colitis associated with diverticulosis, ischemic colitis, or radiation-induced colitis based on medical history, endoscopy, and/or histological findings
* Presence of infectious colitis as evidenced by positive stool culture for enteric pathogens or positive stool Clostridium difficile cytotoxin assay at Visit 1
* Presence of chronic liver disease, with the exception of known Gilbert's syndrome
* A positive pre-study Hepatitis B surface antigen, Hepatitis C antibody or HIV at Visit 1
* Past or present disease that is judged by the investigator to have the potential to interfere with the study procedures or compromise the subject's safety
* History of malignant neoplasm within the past 5 years, other than localized basal cell carcinoma, squamous cell carcinoma, or carcinoma in situ that has been resected or definitively treated with standard approaches
* Prior diagnosis of flat colonic dysplasia or unresected raised colonic dysplasia (adenoma-like lesion or mass)
* History of regular alcohol consumption within 6 months of the Screening (Visit 1) defined as an average weekly intake of \>14 drinks (one drink is defined as 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80 proof distilled spirits) or presence of recreational drug abuse or dependence
* Known bleeding disorders
* Bowel surgery within 12 months prior to Visit 1
* History of colectomy or partial colectomy
* Treatment with oral aminosalicylates at doses \>4.8 g per day or aminosalicylate dose modification (except transient shift lasting up to 3 days) within 4 weeks prior to study Day -5 (Note: if on this type of treatment, the dose must remain constant throughout the study treatment period)
* Treatment with rectal aminosalicylates at any dose within 2 weeks of study Day -5
* Treatment with systemic or rectal corticosteroids within 4 weeks of study Day -5
* Treatment with TNFα inhibitors or other biologics within 2 months prior to study Day -5
* Treatment with other immunosuppressants (azathioprine or 6-mercaptopurine), if initiated within 3 months prior to study Day -5, or if changed in terms of dose within 3 months prior to study Day -5 (Note: if on this type of treatment, the dose must remain constant throughout the study treatment period)
* Regular use of pro-biotic or prebiotic preparations within 4 weeks of study Day -5 visit
* Regular use of non-steroidal anti-inflammatories (NSAIDS) or aspirin, except low dose (cardioprotective ≤325 mg/day) aspirin, within 7 days prior to study Day -5
* Participation in a clinical trial and treatment with an study drug within 3 months prior to Visit 1
* Have a clinically significant finding on a chest X-ray performed at Visit 1 or within 3 months of Visit 1
* Have an abnormal 12-lead electrocardiogram (ECG) with one or more changes considered to be clinically significant on medical review
* Renal or liver impairment based on laboratory values obtained at Visit 1 and defined as:

  * serum creatinine level of ≥1.4 mg/dL for females and ≥1.5 mg/dL for males, or
  * AST and/or ALT ≥2x upper limit of normal (ULN), or
  * bilirubin \> 1.5xULN (an isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%)
  * Hemoglobin less than 8.5 g/dL at Visit 1
  * Have any other reason which, in the opinion of the investigator, would confound the conduct or interpretation of the study

Primary outcomes:
measure: Number of participants with adverse events and incidence of adverse events will be used as a measure of safety and tolerability of 50 mg and 500 mg of SRT2104 after repeat dosing for up to eight weeks in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: SRT2104 concentration in colonic tissue will be measured via endoscopic biopsy after repeat dosing for up to 8 weeks in subjects with mild to moderate ulcerative colitis
timeFrame: 56 days
Secondary outcomes:
measure: Endoscopic scoring of colonic lesions assessed during flexible sigmoidoscopy will be used as a measure of the anti-inflammatory effect of SRT2104 after 8 weeks of treatment in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: Mayo score and Partial Mayo score will be used as a measure of the anti-inflammatory effect of SRT2104 after 8 weeks of treatment in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: Simple Clinical Colitis Activity Index (SCCAI) will be used as a measure of the anti-inflammatory effect of SRT2104 after 8 weeks of treatment in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: Fecal calprotectin will be used as a measure of the anti-inflammatory effect of SRT2104 after 8 weeks of treatment in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: Histopathologic scoring of colonic tissue biopsies obtained via flexible sigmoidoscopy will be used as a measure of the anti-inflammatory effect of SRT2104 after 8 weeks of treatment in subjects with mild to moderate ulcerative colitis
timeFrame: 75 days
measure: SRT2104 concentration in plasma will be measured after repeat dosing for up to 8 weeks in subjects with mild to moderate ulcerative colitis
timeFrame: 56 days
Other outcomes:
Locations:
city: Anaheim
country: United States
facility: GSK Investigational Site
state: California
city: Bristol
country: United States
facility: GSK Investigational Site
state: Connecticut
city: Owensboro
country: United States
facility: GSK Investigational Site
state: Kentucky
city: Chevy Chase
country: United States
facility: GSK Investigational Site
state: Maryland
city: Towson
country: United States
facility: GSK Investigational Site
state: Maryland
city: Chesterfield
country: United States
facility: GSK Investigational Site
state: Michigan
city: Great Neck
country: United States
facility: GSK Investigational Site
state: New York
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Raleigh
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Beavercreek
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oklahoma City
country: United States
facility: GSK Investigational Site
state: Oklahoma
city: Jackson
country: United States
facility: GSK Investigational Site
state: Tennessee
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Sands BE, Joshi S, Haddad J, Freudenberg JM, Oommen DE, Hoffmann E, McCallum SW, Jacobson E. Assessing Colonic Exposure, Safety, and Clinical Activity of SRT2104, a Novel Oral SIRT1 Activator, in Patients with Mild to Moderate Ulcerative Colitis. Inflamm Bowel Dis. 2016 Mar;22(3):607-14. doi: 10.1097/MIB.0000000000000597.