Rosiglitazone

Data for this study were acquired from a recently completed placebo-controlled randomized trial of rosiglitazone for mild to moderately active ulcerative colitis (clinicaltrials.gov #NCT00065065) which has been described in greater detail previously.7 (link) The trial used a slight modification of the Mayo score to assess disease activity (Table 1). Specifically, the bleeding component as described in the Mayo index was modified such that a score of 3 required both visible blood in 50% or more of bowel movements and at least some bowel movements with blood alone.
The study included 105 patients with mild to moderately active disease defined as a total DAI score of 4 to 10, inclusively. Patients were randomized in a 1:1 ratio to receive either rosiglitazone 4 mg or placebo twice daily for 12 weeks. Disease activity was measured at randomization and every four weeks thereafter until week 12, however lower endoscopy was only completed at week 0 and week 12, such that only a partial Mayo score (9 point scale that excludes the endoscopic appearance of the mucosa) could be calculated at the interim visits. In the very early accrual period of the study, a follow-up visit was included at week 2. Without knowledge of the response rates in either arm, the Data and Safety Monitoring Board (DSMB) requested that the week 2 follow-up evaluation be eliminated with the hopes of minimizing the placebo response rate and maximizing recruitment and retention.6 (link), 8 (link), 9 (link) Eighteen patients completed the week 2 follow-up visit.
During the course of the study, patients could be treated with other conventional medications used to treat active ulcerative colitis including mesalamine, oral corticosteroids, immunomodulators, or topical therapies (mesalamine or corticosteroids) at stable doses. Use of corticosteroids at doses greater than 20mg per day of prednisone or the equivalent was an exclusion criterion. Steroid tapering was not permitted during the study.
In anticipation of this sub-study, at each visit we also included questions about change in disease activity compared to the previous visit and compared to the randomization visit on a global seven-point scale (Table 2). The choices included much better, moderately better, a little better, unchanged, a little worse, moderately worse, and much worse. Patients also graded their current disease activity at each visit on a 6 point Likert scale – perfect, very good (minimal symptoms), good (only mild symptoms), moderately active, moderately severe, or severe. Data on quality of life were measured with the Inflammatory Bowel Disease Questionnaire (IBDQ) authored by Dr. Jan Irvine under license from McMaster University, Hamilton, Canada.10 (link)

To assess the transcript variability in a wide panel of samples we put together a set of 180 samples selected to encompass a broad range of adipose tissue origins and experimental conditions (Table 1). Human fat depots were represented by omental, abdominal subcutaneous, and gluteal tissue. The effect of obesity was considered: lean (BMI <25 kg/m²) vs. obese (BMI >30 kg/m²), with equal gender representation. Growth pattern and stimulation of adipogenesis was represented by including surgically removed lipomas vs. normal adjacent adipose tissue and samples taken before and after 14 days of systemic rosiglitazone treatment (4 mg BD) (11 (link)). Methodological issues like biopsy retrieval method (needle vs. surgical) and RNA extraction method (Tri-reagent vs. column) were also included. Finally we prepared differentiated adipocytes from preadipocytes isolated from the stromovascular fraction of subcutaneous biopsies (Table 1). Needle biopsy samples were taken under local anesthesia using a 12-gauge needle and immediately frozen in liquid nitrogen. Surgical biopsies were taken during elective surgery and immediately frozen. Preadipocytes were differentiated and exposed to either 0 μm, 50 μm, or 200 μm palmitate (13 (link)). All biopsies and cells were homogenized in Tri-reagent (cat. no. AM9738, Ambion, Austin, TX) and RNA was extracted with either a standard Tri-reagent protocol or using Ambion MirVana columns (cat. no. AM1561, Ambion).