Impact of patient characteristics on the clinical efficacy of mongersen (GED-0301), an oral Smad7 antisense oligonucleotide, in active Crohn's disease.

BACKGROUND: In a phase 2 study, mongersen, an oral antisense oligonucleotide targeting Smad7, was effective in inducing clinical remission in approximately 60% of patients with active Crohn's disease (CD). AIM: In a post hoc analysis to evaluate those patient disease characteristics that may have influenced the efficacy and safety of mongersen therapy. METHODS: Patients with steroid-dependent/resistant, active CD were randomised to mongersen 10, 40 or 160 mg/day or placebo for 2 weeks; patients were followed for 10 weeks. Clinical remission [Crohn's Disease Activity Index (CDAI) score <150] and clinical response (CDAI score reduction ≥100 points) were assessed at weeks 2, 4 and 12 for these subgroups: disease duration <5/≥5 years, human serum C-reactive protein (hsCRP) <3/≥3 mg/L, and CDAI at baseline ≤260/>260. Additional patient baseline and disease characteristics were explored. RESULTS: Clinical remission and response rates were significantly higher in patients receiving mongersen 40 and 160 mg/day but not 10 mg/day vs. placebo and independent of disease duration and hsCRP. Patients with baseline CDAI ≤260 had significantly higher remission rates with 40 and 160 mg/day. In patients with baseline CDAI >260, remission rates were statistically greater with 160 mg/day and numerically better with 40 mg/day vs. placebo. Adverse event rates were similar across treatment groups. Mongersen was safe and well tolerated. CONCLUSIONS: Patients with higher CDAI scores achieved clinical remission most frequently with the highest mongersen dose. Disease duration and baseline human serum C-reactive protein did not appear to significantly impact efficacy of mongersen in this study (EudraCT Number: 2011-002640-27.).

Long-term efficacy and safety of canagliflozin over 104 weeks in patients aged 55-80 years with type 2 diabetes.

AIMS: The long-term efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, was evaluated over 104 weeks in patients aged 55-80 years with type 2 diabetes mellitus (T2DM) inadequately controlled on a stable antihyperglycaemic agent regimen. METHODS: In this randomized, double-blind, phase III study, patients received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period (N = 714) and a 78-week extension period (n = 624). Efficacy endpoints at week 104 included change from baseline in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG) and systolic blood pressure, and percent change from baseline in body weight and fasting plasma lipids. Safety was assessed by adverse event (AE) reports. RESULTS: At week 104, canagliflozin 100 and 300 mg were associated with reductions in HbA1c versus placebo (-0.32 and -0.43% vs 0.17%, respectively; overall mean baseline, 7.7%) and more patients achieved HbA1c <7.0% with canagliflozin 100 and 300 mg than with placebo (35.8 and 41.9% vs 20.3%, respectively). Reductions in FPG, body weight and systolic blood pressure, and increases in high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) were seen with canagliflozin compared with placebo. The overall incidence rates of AEs over 104 weeks were 88.0, 89.8 and 86.1% with canagliflozin 100 and 300 mg and placebo, respectively; serious AE rates were low across treatment groups. The incidence rates of urinary tract infections, genital mycotic infections and osmotic diuresis- and volume depletion-related AEs were higher with canagliflozin than with placebo. CONCLUSION: Canagliflozin improved glycaemic control, reduced body weight and systolic blood pressure, and was generally well tolerated in patients aged 55-80 years with T2DM over 104 weeks.

Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease.

AIM: This study evaluated the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus (T2DM) and within a subset of Stage 3 chronic kidney disease (CKD; estimated glomerular filtration rate [eGFR] ≥ 30 and <50 ml/min/1.73 m(2)). METHODS: In this 52-week, randomized, double-blind, placebo-controlled study, patients (N = 269; mean eGFR, 39.4 ml/min/1.73 m(2)) received canagliflozin 100 or 300 mg and placebo once daily. Efficacy endpoints included changes in glycated haemoglobin (HbA1c), fasting plasma glucose (FPG), body weight and systolic blood pressure (BP); adverse events (AEs) were also recorded. RESULTS: At week 52, canagliflozin 100 and 300 mg reduced HbA1c compared with placebo (-0.19, -0.33 and 0.07%, respectively); placebo-subtracted differences (95% confidence interval) were -0.27% (-0.53, 0.001) and -0.41% (-0.68, -0.14). Canagliflozin also lowered FPG, body weight and BP versus placebo. Overall AE incidence was 85.6, 80.9, and 86.7% with canagliflozin 100 and 300 mg and placebo, respectively. Osmotic diuresis-related AEs were more common with both canagliflozin doses, and incidences of urinary tract infections and volume depletion-related AEs were higher with canagliflozin 300 mg versus placebo. Decreases in eGFR (-2.1, -4.0 and -1.6 ml/min/1.73 m(2)) were seen with canagliflozin 100 and 300 mg compared with placebo. Canagliflozin 100 and 300 mg provided median percent reductions in urine albumin to creatinine ratio versus placebo (-16.4, -28.0 and 19.7%). CONCLUSIONS: Canagliflozin improved glycaemic control and was generally well tolerated in patients with T2DM and within a subset of Stage 3 CKD over 52 weeks.

Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor developed for the treatment of type 2 diabetes mellitus (T2DM). This randomised, double-blind, placebo-controlled, Phase 3 study evaluated the efficacy and safety of canagliflozin as an add-on to metformin plus sulphonylurea in patients with T2DM. METHODS: Patients (N = 469) received canagliflozin 100 or 300 mg or placebo once daily during a 26-week core period and a 26-week extension. Prespecified primary end-point was change in HbA1c at 26 weeks. Secondary end-points included change in HbA1c at week 52 as well as proportion of patients achieving HbA1c < 7.0%, change in fasting plasma glucose (FPG) and systolic blood pressure, and per cent change in body weight, high-density lipoprotein cholesterol, and triglycerides (weeks 26 and 52). RESULTS: HbA1c was significantly reduced with canagliflozin 100 and 300 mg vs. placebo at week 26 (-0.85%, -1.06%, and -0.13%; p < 0.001); these reductions were maintained at week 52 (-0.74%, -0.96%, and 0.01%). Both canagliflozin doses reduced FPG and body weight vs. placebo at week 26 (p < 0.001) and week 52. Overall adverse event (AE) rates were similar across groups over 52 weeks, with higher rates of genital mycotic infections and osmotic diuresis-related AEs seen with canagliflozin vs. placebo; these led to few discontinuations. Increased incidence of documented, but not severe, hypoglycaemia episodes was seen with canagliflozin vs. placebo. CONCLUSIONS: Canagliflozin improved glycaemic control, reduced body weight, and was generally well tolerated in T2DM patients on metformin plus sulphonylurea over 52 weeks.

Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for treatment of type 2 diabetes mellitus (T2DM). This study evaluated the efficacy and safety of canagliflozin in subjects with T2DM and stage 3 chronic kidney disease [CKD; estimated glomerular filtration rate (eGFR) ≥30 and <50 ml/min/1.73 m(2)]. METHODS: In this randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 269) received canagliflozin 100 or 300 mg or placebo daily. The primary efficacy endpoint was change from baseline in HbA1c at week 26. Prespecified secondary endpoints were change in fasting plasma glucose (FPG) and proportion of subjects reaching HbA1c <7.0%. Safety was assessed based on adverse event (AE) reports; renal safety parameters (e.g. eGFR, blood urea nitrogen and albumin/creatinine ratio) were also evaluated. RESULTS: Both canagliflozin 100 and 300 mg reduced HbA1c from baseline compared with placebo at week 26 (-0.33, -0.44 and -0.03%; p < 0.05). Numerical reductions in FPG and higher proportions of subjects reaching HbA1c < 7.0% were observed with canagliflozin 100 and 300 mg versus placebo (27.3, 32.6 and 17.2%). Overall AE rates were similar for canagliflozin 100 and 300 mg and placebo (78.9, 74.2 and 74.4%). Slightly higher rates of urinary tract infections and AEs related to osmotic diuresis and reduced intravascular volume were observed with canagliflozin 300 mg compared with other groups. Transient changes in renal function parameters that trended towards baseline over 26 weeks were observed with canagliflozin. CONCLUSION: Canagliflozin improved glycaemic control and was generally well tolerated in subjects with T2DM and Stage 3 CKD.

Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise.

AIMS: Canagliflozin is a sodium glucose co-transporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The efficacy and safety of canagliflozin were evaluated in subjects with T2DM inadequately controlled with diet and exercise. METHODS: In this 26-week, randomized, double-blind, placebo-controlled, phase 3 trial, subjects (N = 584) received canagliflozin 100 or 300 mg or placebo once daily. Primary endpoint was the change from baseline in haemoglobin A1c (HbA1c) at week 26. Secondary endpoints included the proportion of subjects achieving HbA1c < 7.0%; change from baseline in fasting plasma glucose (FPG), 2-h postprandial glucose (PPG) and systolic blood pressure (BP); and percent change in body weight, high-density lipoprotein cholesterol (HDL-C) and triglycerides. Adverse events (AEs) were recorded throughout the study. RESULTS: At week 26, HbA1c was significantly reduced from baseline with canagliflozin 100 and 300 mg compared with placebo (-0.77, -1.03 and 0.14%, respectively; p < 0.001 for both). Both canagliflozin doses significantly decreased FPG, 2-h PPG, body weight and systolic BP (p < 0.001 for all), and increased HDL-C compared with placebo (p < 0.01 for both). Overall incidences of AEs were modestly higher with canagliflozin versus placebo; rates of serious AEs and AE-related discontinuations were low and similar across groups. Incidences of genital mycotic infections, urinary tract infections and osmotic diuresis-related AEs were higher with canagliflozin; these led to few discontinuations. The incidence of hypoglycaemia was low across groups. CONCLUSION: Canagliflozin treatment improved glycaemic control, reduced body weight and was generally well tolerated in subjects with T2DM inadequately controlled with diet and exercise.

Effect of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, on bacteriuria and urinary tract infection in subjects with type 2 diabetes enrolled in a 12-week, phase 2 study.

OBJECTIVE: To examine the effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor that lowers blood glucose by increasing urinary glucose excretion (UGE), on asymptomatic bacteriuria and urinary tract infections (UTIs). RESEARCH DESIGN AND METHODS: In a randomized, double-blind, placebo-controlled, multicenter, dose-ranging phase 2 study, subjects with type 2 diabetes with inadequate glycemic control while receiving metformin were enrolled and randomized to one of seven arms - placebo; canagliflozin doses 50 mg, 100 mg, 200 mg, 300 mg daily, or 300 mg twice daily; and sitagliptin 100 mg daily - for 12 weeks. CLINICAL TRIAL REGISTRATION: This study is registered under Clinicaltrials.gov identification number NCT00642278. RESULTS: Canagliflozin increased renal glucose excretion by 35.4-61.6 mg/mg creatinine in the five dose groups. In the placebo group renal glucose excretion was increased by 1.9 mg/mg creatinine, and in the sitagliptin group it decreased by 1.9 mg/mg creatinine. Asymptomatic bacteriuria (ASB) were present in 6.4% of canagliflozin and 6.5% of placebo/sitagliptin (control) subjects at randomization and, at 12 weeks, in 7.7% and 6.3% of subjects, respectively (odds ratio [OR] 1.23; 95% confidence interval [CI], 0.45-3.89). For subjects with initially negative urine cultures at baseline, 3 out of 82 (3.7%) who received controls and 10 out of 207 (4.8%) who received canagliflozin developed bacteriuria (p = 0.76) at week 12. There were 21 adverse event (AE) reports of UTI; 16 (5.0%) in canagliflozin subjects and 5 (3.8%) in control subjects (OR 1.31; 95% CI, 0.45-4.68). CONCLUSIONS: In this trial, when compared with control subjects, canagliflozin increased UGE but was not associated with increased bacteriuria or AE reports of UTI. However, further studies enrolling larger numbers of subjects with longer term exposure to canagliflozin will be necessary to more fully understand the impact of this agent on the risk of developing UTI.

T lymphocyte surface antigen markers in osteoporosis.

Two distinct syndromes of osteoporosis have been postulated: type I, which is characterized by accelerated bone loss occurring in women during the early postmenopausal period; and type II, an age-related process of bone loss affecting both men and women in and after the seventh decade. Recently there has been indirect evidence linking local products of the immune system with bone remodeling. We therefore studied peripheral blood profiles of specific lymphocyte phenotypes in women with type I osteoporosis and in older women and men with type II osteoporosis. The ratio of CD4-bearing (T helper) cells to CD8-bearing (T cytotoxic-suppressor) cells (CD4/CD8 ratio) was elevated in women with symptomatic type I disease. In addition there was a significant negative correlation (r = -0.62, P less than 0.001) between the CD4/CD8 ratio and the spinal bone mineral density measured by dual-photon absorptiometry. In contrast, older men with a history of fracture (hip or spine) had CD4/CD8 ratios similar to control men. The number of T cells bearing IL-2R or VLA-1 was not different between osteoporotic subjects and controls in either men or women. This study supports the concept that local products of the immune system may be directly or indirectly involved in the pathogenesis of type I osteoporosis.

Lack of effect of dehydroepiandrosterone in obese men.

To assess the effects of dehydroepiandrosterone (DHEA) on weight and body fat mass in young obese men, six obese (body mass index, 31.5 +/- 2.9 (s.e.] men were studied at baseline, after 28 days of placebo administration, and again after 28 days of DHEA (1600 mg/day) administration. Body fat mass was assessed on each occasion by three separate methods: hydrostatic weighing, impedance plethysmography, and skinfold measurements at four body sites. Waist-to-hip ratios were recorded. In addition, tissue sensitivity to insulin was determined using the modified minimal model technique, and serum lipids were assayed. Serum DHEA-sulfate levels rose from 7.4 +/- 1.7 mumol/l at baseline to 39.8 +/- 11.9 mumol/l after DHEA administration (P less than 0.05). Although body fat mass was reduced in two of the six men following DHEA administration, for the group as a whole neither total body weight, body fat mass, or waist-to-hip ratio changed significantly during the study. No change in either tissue insulin sensitivity or serum lipids was observed. These observations suggest that, at a daily dose of 13.4-19.7 mg/kg, short-term DHEA administration does not affect the total weight, body fat mass, fat distribution, insulin sensitivity, or lipid status of obese young men.

Suppression of serum dehydroepiandrosterone sulfate levels by insulin: an evaluation of possible mechanisms.

We previously demonstrated a progressive decline in serum dehydroepiandrosterone sulfate (DHEA-S) levels in women during a hyperinsulinemic-euglycemic clamp. To determine whether this fall in serum DHEA-S levels might have been due to insulin-stimulated 1) hydrolysis of DHEA-S to dehydroepiandrosterone (DHEA), 2) conversion of DHEA-S/DHEA to androstenedione, and/or 3) urinary excretion of these steroids, 10 additional men were studied by the hyperinsulinemic-euglycemic clamp technique. Each man received a 0.1 U/kg (0.72 nmol/kg) insulin bolus dose, followed by a 10 mU/kg.min (72 pmol/kg.min) insulin infusion for 4 h. An average insulin level of 12,390 +/- 259 (+/- SE) pmol/L (1,726.8 +/- 36 microU/mL) was achieved; serum glucose was maintained at 5.0 +/- 0.1 mmol/L (90.5 +/- 2.3 mg/dL). During the hyperinsulinemia, serum DHEA-S levels fell progressively and were significantly lower than baseline at 4 and 6 h of study (85.5 +/- 5.9% and 79.1 +/- 3.2% of baseline values, respectively; P less than 0.05). Serum DHEA levels fell concurrently and were significantly lower than baseline at 2, 4, and 6 h of study (66.2 +/- 12.3%, 61.6 +/- 11.2%, and 52.9 +/- 10.2% of baseline values, respectively; P less than 0.05). The percent fall in serum DHEA levels correlated positively with the percent fall in serum DHEA-S levels (r = 0.44; P less than 0.02). Serum androstenedione levels also fell progressively during hyperinsulinemia and were significantly lower than baseline at 2, 4, and 6 h of study (71.5 +/- 4.1%, 71.0 +/- 7.2%, and 48.1 +/- 3.3% of baseline values, respectively; P less than 0.05). No change in serum DHEA-S, DHEA, or androstenedione levels occurred in paired control studies, during which 0.45% saline was infused at rates matched exactly to the rates of the dextrose and insulin infusions during the hyperinsulinemic clamp studies. Despite decreasing serum DHEA-S and DHEA levels during hyperinsulinemia, urinary DHEA-S and DHEA glucuronide excretions were increased by 50% (P less than 0.05) and 86% (P = 0.05), respectively, compared to urinary excretion of these steroids during control studies. In contrast, urinary excretion of unconjugated DHEA was unchanged. Quantitatively, however, increased urinary excretion of conjugated DHEA during hyperinsulinemia accounted for only about 5% of the concomitant fall in serum DHEA-S concentrations.(ABSTRACT TRUNCATED AT 400 WORDS)