Study to Evaluate the Pharmacodynamics of SB-656933 in Patients With Ulcerative Colitis

An Open Label, 7-day Repeat Dose Study to Evaluate the Pharmacodynamics of SB-656933-AAA in Patients With Ulcerative Colitis.

This study will involve the use of a new compound, SB-656933. Accumulation of inflammatory white blood cells (mostly polymorphonuclear neutrophils)in the gut (colon) may be contributing to the pathology of ulcerative colitis. It has been shown that SB-656933 reduces polymorphonuclear neutrophils (PMN) accumulation in pre-clinical models of colitis. 99m-Tc-HMPAO scintigraphy is a imaging technique which will be used in this study to observe the effect of SB656933 on the migration of PMN to inflamed tissue.

Study Overview

• Status: Terminated
• Conditions: Colitis, Ulcerative
• Intervention / Treatment: Drug: SB-656933

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

• A history of ulcerative colitis for at least 3 months
• moderately active UC, either stable on medications or in a flare of the disease
• Mayo endoscopic score of 2 or 3 within 2 days of dosing.
• Male or female between 18 and 65 years of age
• Women of child bearing potential must use an effective method of contraception.
• Male subjects must agree to use one of the specified contraception method,
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) normal at study start.
• Signed written informed consent
• QTcB or QTcF < 450msec at screening

Exclusion criteria:

• The subject has a positive pre-study drug/alcohol screen.
• A positive test for HIV, hepatitis B or C.
• History of regular alcohol consumption within 6 months of the study
• Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements within 7 days or 5 half-lives prior to the first dose of study medication
• Known allergies
• recent participation in another trial
• recent blood donation
• Pregnant or lactating females
• unwillingness or inability to follow study procedures
• consumption of red wine, seville oranges, grapefruit or grapefruit juice in last 7 seven day before study start.
• Mild UC, Mayo endoscopic score of 0 or 1.
• Toxic megacolon or perforation on plain abdominal Xray.
• Crohn's Disease, indeterminate colitis, bleeding disorders, or active ulcer disease.
• Previous colonic surgery.
• Current or recurrent disease, other than UC, that could affect the action, absorption or disposition of the study medication, or clinical or laboratory assessments.
• Absolute neutrophil count below 2.0x109/L.
• A positive culture for enteric pathogens that is clinically significant, presence of clostridium difficile toxin, or with ova and parasites detected by microscopy, or has a clinical suspicion of an infectious disease of the bowel.
• Symptomatic GI stricture within 6 months of screening or obstructive symptoms within 3 months of screening.
• Likely to require abdominal surgery within the study period.
• Congenital or acquired immunodeficiency, including any immunologic diseases with gastrointestinal involvement except for UC.
• Ongoing neoplastic disease of the bowel.
• History of prostatitis, epididymitis, epididymal cysts, structural abnormalities or testicular cancer.
• Subjects with abnormalities of the renal tract, renal stones or history of recurrent urinary tract infections (UTI.s).
• Subjects with any history of autoimmune hepatitis or sclerosing cholangitis. Previous inclusion in a research and/or medical protocol involving nuclear medicine, PET or radiological investigations with significant radiation burden.
• Blood pressure persistently ≥ 140/90 mmHg at screening
• Concurrent illness or disability that may affect the interpretation of clinical data, or otherwise contraindicates participation in this clinical study (e.g., an unstable cardiovascular, autoimmune, renal, pulmonary, hepatic, endocrine, metabolic, haematological, or neurological condition).
• Clinically significant hepatic impairment(Evidence of cirrhosis, Clinical episodes of jaundice)
• Current evidence of, or has been treated for a malignancy within the past 5 years.
• BMI <18 kg.m2 or >35 kg/m2
• Clinically significant renal laboratory values.
• Has not discontinued any prohibited concomitant medication prior to the screening visit or within the protocol-specified time period.
• Has not remained on a stable dose of any permitted concomitant medication(s) for the protocol-specified time period preceding the Screening Visit.
• history of substance abuse

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 7 Days Repeat Dose	Drug: SB-656933; 7 days repeat dose; Other Names: SB656933

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline at 1 and 7 Days Treatment With Daily Dose of SB-656933-AAA in 99m(Technetium-hexamethyl Derivative of Propylene Amine Oxide)Tc-HMPAO Leukocyte Single Photon Emission Computerized Tomography (SPECT) Scintigraphic Activity Scores (SAS)	Data has been presented for participants since change from Baseline data was not analyzed. For scintigraphy, blood was obtained for radiolabelling. Labelled white cells were then injected for SPECT scintigraphy and scanning began 45 minutes after injection of labelled White blood cells (WBCs). SPECT images of the colon were divided into 5 segments: ascending colon, transverse colon, descending colon, sigmoid, and rectum.T he SPECT segment uptake ratio was expressed as a fraction of bone marrow activity obtained from counts in the lumbar spine. The SPECT segment uptake ratio was converted into a four-point (0 to 3) segmental SPECT severity score where grade 0 was equal to no uptake. Only 3 participants were included before the study was discontinued.It was not possible to draw any meaningful conclusions from the very limited data available. Data has been presented for the 3 participants (99001, 99002 and 99003) since the analysis was not done. Baseline was Day -1.	Baseline (Day -1) and Day 1 and 7

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was defined as any untoward medical occurrence that occurred during the course of the trial after study treatment had started. An adverse event was therefore any unfavorable and unintended sign, symptom, or disease temporally associated with the use of study drug, whether or not considered related to the study drug. An SAE was any untoward medical occurrence that at any dose results in death, are life threatening, requires hospitalization or prolongation of hospitalization or results in disability/incapacity, and congenital anomaly/birth defect.	Up to follow-up (7 to 10 days after last dose)
Vital Signs Assessment- Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP)	Vital sign measurements included SBP and DBP at Day 1 and 7. Data was collected in supine position. It was not possible to draw any meaningful conclusions from the very limited data available. Data has been presented for the 3 participants (99001, 99002 and 99003) since the analysis was not done.	Day 1 and 7
Vital Signs Assessment- Heart Rate	Vital sign measurements included heart rate at Day 1 and 7. Data was collected in supine position. It was not possible to draw any meaningful conclusions from the very limited data available. Data has been presented for the 3 participants (99001, 99002 and 99003) since the analysis was not done.	Day 1 and 7
Changes From Baseline to After Treatment in Faecal Calprotectin Levels	Stool sample was collected from 1-hour post dose until 8 hours post dose for faecal calprotectin measures. It was not possible to draw any meaningful conclusions from the very limited data available. Data has been presented for the 3 participants (99001, 99002 and 99003) since the analysis was not done. Baseline was Day -1.	Day -1 and pre-dose and 8 hour post-dose on Day 1 and 7
Amount of Medicine in Blood	Blood samples were collected at 1, 2.25, 4, 8 hour on Day 1 and 7 for the analysis of amount of medicine in blood. It was not possible to draw any meaningful conclusions from the very limited data available. Data has been presented for the 3 participants (99001, 99002 and 99003) since the analysis was not done.	At 1, 2.25, 4, 8 hour on Day 1 and 7

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 22, 2009
• Primary Completion (ACTUAL): December 12, 2009
• Study Completion (ACTUAL): December 12, 2009

Study Registration Dates

• First Submitted: September 5, 2008
• First Submitted That Met QC Criteria: September 5, 2008
• First Posted (ESTIMATE): September 8, 2008

Study Record Updates

• Last Update Posted (ACTUAL): October 30, 2020
• Last Update Submitted That Met QC Criteria: October 8, 2020
• Last Verified: October 1, 2020

More Information

Terms related to this study

• Keywords: Ulcerative colitis; CD11b; 99mTc-HMPAO-labelled leukocyte scintigraphy
• 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: CUC111342; 2007-005520-32 (EUDRACT_NUMBER)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO