A Phase 1b Study to Assess the Safety and Anti-inflammatory Effects of Two Different Doses of SRT2104 in Patients With Ulcerative Colitis

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

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.

Study Overview

• Status: Completed
• Conditions: Colitis, Ulcerative
• Intervention / Treatment: Drug: SRT2104

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Anaheim, California, United States, 92801
      • GSK Investigational Site
  • Connecticut
    • Bristol, Connecticut, United States, 06010
      • GSK Investigational Site
  • Kentucky
    • Owensboro, Kentucky, United States, 42303
      • GSK Investigational Site
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • GSK Investigational Site
    • Towson, Maryland, United States, 21204
      • GSK Investigational Site
  • Michigan
    • Chesterfield, Michigan, United States, 48047
      • GSK Investigational Site
  • New York
    • Great Neck, New York, United States, 11021
      • GSK Investigational Site
    • New York, New York, United States, 10029
      • GSK Investigational Site
  • North Carolina
    • Raleigh, North Carolina, United States, 27612
      • GSK Investigational Site
  • Ohio
    • Beavercreek, Ohio, United States, 45432
      • GSK Investigational Site
    • Columbus, Ohio, United States, 43215
      • GSK Investigational Site
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • GSK Investigational Site
  • Tennessee
    • Jackson, Tennessee, United States, 38305
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 50mg SRT2104; Single oral administration of 50mg SRT2104 study drug will be supplied as 25 mg and 250 mg capsules and will be taken orally once daily for 56 days. SRT2104 is to be taken at approximately the same time every morning, in the fasted state. Water is permitted ad libitum. Subjects are allowed to consume liquids but should refrain from eating solid food for approximately 1 hour after dosing.	Drug: SRT2104; SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 25mg or 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule. All subjects will be provided with one dosing bottle per day that contains two 25 mg or 250 mg SRT2104 capsules for oral ingestion.
Experimental: 500mg SRT2104; Single oral administration of 500mg SRT2104 will be taken orally once daily for 56 days. SRT2104 is to be taken at approximately the same time every morning, in the fasted state. Water is permitted ad libitum. Subjects are allowed to consume liquids but should refrain from eating solid food for approximately 1 hour after dosing.	Drug: SRT2104; SRT2104 drug substance is a new chemical entity which is supplied as a fine, yellowish/amber powder. The SRT2104 investigational product is prepared by packing 25mg or 250 mg of micronized SRT2104 powder with no additional additives into a size 00 opaque, hard gelatin capsule. All subjects will be provided with one dosing bottle per day that contains two 25 mg or 250 mg SRT2104 capsules for oral ingestion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
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	75 days
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	56 days

Secondary Outcome Measures

Outcome Measure	Time Frame
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	75 days
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	75 days
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	75 days
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	75 days
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	75 days
SRT2104 concentration in plasma will be measured after repeat dosing for up to 8 weeks in subjects with mild to moderate ulcerative colitis	56 days

Collaborators and Investigators

• Sponsor: Sirtris, a GSK Company
• Collaborators: GlaxoSmithKline

Publications and helpful links

General Publications

• 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.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start (Actual): February 13, 2012
• Primary Completion (Actual): March 18, 2013
• Study Completion (Actual): March 18, 2013

Study Registration Dates

• First Submitted: October 13, 2011
• First Submitted That Met QC Criteria: October 13, 2011
• First Posted (Estimate): October 18, 2011

Study Record Updates

• Last Update Posted (Actual): June 1, 2017
• Last Update Submitted That Met QC Criteria: May 31, 2017
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative
• Other Study ID Numbers: 115951

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Study Protocol
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Clinical Study Report
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Individual Participant Data Set
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Statistical Analysis Plan
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Informed Consent Form
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Annotated Case Report Form
   Information identifier: 115951
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register