Clinical trials in youth-onset type 2 diabetes: needs, barriers, and options.

Youth-onset type 2 diabetes (T2D) is increasingly recognized as a disorder with substantial risk for long-term metabolic, cardiovascular, and renal morbidity and mortality, as well as individual and societal burden. Recent studies suggest that the disorder differs from adult-onset T2D in a variety of ways and that there is an urgent need for an expanded set of treatment options. However, demographic, economic, and social challenges limit the number of eligible candidates for clinical trials in youth-onset T2D, and a growing number trials mandated by regulatory agencies have created a circumstance in which too many trials are chasing too few eligible participants. A solution to this situation will require novel approaches to clinical trial design incorporating collaboration among clinical investigators, pharmaceutical sponsors, and regulatory agencies. If successful, this approach could also serve as a model for clinical trials in other rare and understudied pediatric disorders.

Effect of colesevelam HCl monotherapy on lipid particles in type 2 diabetes mellitus.

PURPOSE: In addition to lowering hemoglobin A1C, colesevelam has been shown to improve the atherogenic lipoprotein profile of subjects with type 2 diabetes mellitus (T2DM) when used in combination with metformin and/or sulfonylureas. A recent study evaluated the effects of colesevelam as antidiabetes monotherapy in adults with T2DM who had inadequate glycemic control (hemoglobin A1C ≥7.5 to ≤9.5 %) with diet and exercise alone; we report here the effects on lipoprotein particle subclasses. METHODS: Subjects were randomized to receive oral colesevelam 3.75 g/day (n = 176) or placebo (n = 181) for 24 weeks. Changes in lipoprotein particle subclasses were determined by nuclear magnetic resonance spectroscopy. RESULTS: At Week 24 with last observation carried forward, colesevelam produced a reduction in total low-density lipoprotein (LDL) particle concentration (baseline: 1,611 nmol/L; least-squares [LS] mean treatment difference: -143 nmol/L, p < 0.0001) versus placebo; reductions were also seen in large, small, and very small LDL particle concentrations (all p < 0.05). There was also a reduction in total very low-density lipoprotein (VLDL) and chylomicron particle concentration (baseline: 88 nmol/L; LS mean treatment difference: -1 nmol/L, p = 0.82) that resulted from a lowering in small VLDL particle concentration (baseline: 45 nmol/L; LS mean treatment difference: -5 nmol/L, p = 0.03). In addition, with colesevelam there was an increase in total high-density lipoprotein (HDL) particle concentration versus placebo (baseline: 31 µmol/L; LS mean treatment difference: +0.6 µmol/L, p = 0.20), due to increases in the large (baseline: 5 µmol/L; LS mean treatment difference: +0.5 µmol/L, p = 0.007) and medium (baseline: 3 µmol/L; LS mean treatment difference: +0.8 µmol/L, p = 0.02) HDL subclasses. CONCLUSIONS: Colesevelam monotherapy in subjects with T2DM resulted in generally favorable changes in certain lipoprotein subclass profiles compared with placebo.

Phase I studies of the safety, tolerability, pharmacokinetics, and pharmacodynamics of DS-1211, a tissue-nonspecific alkaline phosphatase inhibitor.

Tissue-nonspecific alkaline phosphatase (TNAP) hydrolyzes and inactivates inorganic pyrophosphate (PPi), a potent inhibitor of calcification; therefore, TNAP inhibition is a potential target to treat ectopic calcification. These two first-in-human studies evaluated safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of single (SAD) and multiple-ascending doses (MAD) of DS-1211, a TNAP inhibitor. Healthy adults were randomized 6:2 to DS-1211 or placebo, eight subjects per dose cohort. SAD study subjects received one dose of DS-1211 (range, 3-3000 mg) or placebo, whereas MAD study subjects received DS-1211 (range, 10-300 mg) once daily, 150 mg twice daily (b.i.d.), or placebo for 10 days. Primary end points were safety and tolerability. PK and PD assessments included plasma concentrations of DS-1211, alkaline phosphatase (ALP) activity, and TNAP substrates (PPi, pyridoxal 5'-phosphate [PLP], and phosphoethanolamine [PEA]). A total of 56 (DS-1211: n = 42; placebo: n = 14) and 40 (DS-1211: n = 30; placebo: n = 10) subjects enrolled in the SAD and MAD studies, respectively. In both studies, adverse events were mild or moderate and did not increase with dose. PKs of DS-1211 were linear up to 100 mg administered as a single dose and 150 mg b.i.d. administered as a multiple-dose regimen. In multiple dosing, there was minimal accumulation of DS-1211. Increased DS-1211 exposure correlated with dose-dependent ALP inhibition and concomitant increases in PPi, PLP, and PEA. In two phase I studies, DS-1211 appeared safe and well-tolerated. Post-treatment PD assessments were consistent with exposure-dependent TNAP inhibition. These data support further evaluation of DS-1211 for ectopic calcification diseases.

Low-dose rosiglitazone in patients with insulin-requiring type 2 diabetes.

BACKGROUND: The objective was to compare the efficacy and safety of adding low-dose rosiglitazone (2 or 4 mg/d) to insulin therapy vs continued insulin monotherapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with insulin therapy alone. METHODS: In this 24-week, double-blind study, 630 individuals with type 2 diabetes mellitus that was inadequately controlled with insulin therapy alone were randomized to treatment with rosiglitazone (2 or 4 mg/d) or placebo in combination with ongoing insulin therapy. The dosage of insulin therapy could be adjusted at the investigator's discretion if required for hypoglycemia or additional glycemic control. RESULTS: The addition of rosiglitazone (2 or 4 mg/d) to insulin therapy significantly decreased mean glycated hemoglobin concentrations compared with placebo plus insulin (-0.3% [P=.02] and -0.4% [P<.001]) and compared with baseline (-0.6% and -0.8% [both P<.001]) after 24 weeks. The addition of 2 or 4 mg/d of rosiglitazone significantly decreased the C-reactive protein level (vs baseline: -22.0% [P<.001] and -34.2% [P<.001]; vs placebo: -22.2% [P=.003] and -32.0% [P<.001]) and fibrinogen (vs baseline: -10.5% and -12.0% [both P<.001]; vs placebo: -7.9% [P=.002] and -7.6% [P=.004]), while 4 mg/d of rosiglitazone significantly reduced matrix metalloproteinase 9 levels (vs baseline: -17.1% [P=.007]; vs placebo: -23.3% [P<.001]). The adverse event profile, including incidence of hypoglycemia and edema, was similar between treatment groups, and most adverse events were mild to moderate in intensity. CONCLUSIONS: The addition of low-dose rosiglitazone to insulin therapy is an effective and well-tolerated treatment option for patients with type 2 diabetes mellitus who continue to have poor glycemic control despite administration of exogenous insulin as monotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00054782.

Glucose-lowering effects and safety of DS-8500a, a G protein-coupled receptor 119 agonist, in Japanese patients with type 2 diabetes: results of a randomized, double-blind, placebo-controlled, parallel-group, multicenter, phase II study.

OBJECTIVE: DS-8500a is a novel G protein-coupled receptor 119 agonist being developed for the treatment of type 2 diabetes. The study objective was to assess the efficacy and safety of DS-8500a in Japanese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: In this double-blind, parallel-group, phase II study, 99 Japanese patients with type 2 diabetes were randomized to receive placebo, or DS-8500a 10 mg or 75 mg once daily for 28 days. The primary efficacy endpoint was change in the 24-hour weighted mean glucose (WMG) from baseline (day -1) to day 28. Other endpoints included changes in fasting plasma glucose, postprandial glucose, lipids, and safety. RESULTS: The 24-hour WMG decreased significantly after 28 days of treatment in the 10 mg and 75 mg groups with placebo-subtracted least squares mean differences (95% CI) of -0.74 (-1.29 to -0.19) mmol/L and -1.05 (-1.59 to -0.50) mmol/L, respectively. Reductions in 24-hour WMG in both DS-8500a groups were observed on day 14 and were greater on day 28 than on day 14. The reductions in fasting plasma glucose and 2-hour postprandial glucose were significantly greater in the 75 mg DS-8500a group versus placebo. Total cholesterol, low-density lipoprotein cholesterol, and triglycerides decreased significantly; high-density lipoprotein cholesterol increased significantly in the 75 mg group versus placebo. Both doses of DS-8500a were well tolerated without significant treatment-related adverse events, hypoglycemia, or discontinuations due to adverse events. CONCLUSIONS: DS-8500a significantly improved glycemic control and lipids and was well tolerated over 28 days of administration in Japanese patients with type 2 diabetes. TRIAL REGISTRATION NUMBER: NCT02222350; Post-results.

A 26-week, placebo- and pioglitazone-controlled, dose-ranging study of rivoglitazone, a novel thiazolidinedione for the treatment of type 2 diabetes.

OBJECTIVE: To examine the efficacy and general safety of rivoglitazone, a novel thiazolidinedione, as a treatment for type 2 diabetes in a dose-ranging study over a period of up to 6 months. RESEARCH DESIGN AND METHODS: A 26-week, randomized, double-blind, double-dummy, placebo- and active comparator (pioglitazone 45 mg)-controlled study designed to evaluate the efficacy and safety of once-daily rivoglitazone 1, 2, or 3 mg in subjects with type 2 diabetes. The study was conducted in adults with type 2 diabetes (glycated hemoglobin [HbA(1c)] >or=7.0% and <10.5%) who were either naïve to prior antidiabetes drug treatment or discontinued pre-study antidiabetes medications and were switched to study medication. A total of 441 subjects were randomized, using an equal allocation schedule to one of five treatment arms, including placebo. The primary efficacy measurement was the change in HbA(1c) from baseline to week 26 in the intent-to-treat population (last observation carried forward), for drug treatments minus placebo (placebo-subtracted). CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT00143520. RESULTS: The incidence of early discontinuations was >50%, with most cases being related to a lack of efficacy (highest on placebo) or adverse experiences (highest on rivoglitazone 3 mg). Rivoglitazone 1, 2, and 3 mg and pioglitazone 45 mg were more effective than placebo in reducing HbA(1c) from baseline to week 26 (placebo-subtracted change from baseline: -0.55% [p = 0.0034], -0.99% [p < 0.0001], -1.10% [p < 0.0001], and -0.59% [p = 0.0016], respectively). In general, all treatments were safe. The most common drug-related adverse events reported with rivoglitazone were peripheral edema and weight gain; incidences increased with dose and were higher with rivoglitazone 2 and 3 mg than with pioglitazone or rivoglitazone 1 mg. CONCLUSIONS: Rivoglitazone is a potent thiazolidinedione agent with demonstrated glycemic benefits over a 6-month period in subjects with type 2 diabetes. Once-daily doses of 1, 2, and 3 mg rivoglitazone demonstrated HbA(1c) reduction similar or superior to those observed for pioglitazone 45 mg. Limitations in generalizing from this study include a modest sample size and a high rate of discontinuation prior to the last scheduled visit.

Phosphorylation by cyclin C/cyclin-dependent kinase 2 following mitogenic stimulation of murine fibroblasts inhibits transcriptional activity of LSF during G1 progression.

Transcription factor LSF is required for progression from quiescence through the cell cycle, regulating thymidylate synthase (Tyms) expression at the G(1)/S boundary. Given the constant level of LSF protein from G(0) through S, we investigated whether LSF is regulated by phosphorylation in G(1). In vitro, LSF is phosphorylated by cyclin E/cyclin-dependent kinase 2 (CDK2), cyclin C/CDK2, and cyclin C/CDK3, predominantly on S309. Phosphorylation of LSF on S309 is maximal 1 to 2 h after mitogenic stimulation of quiescent mouse fibroblasts. This phosphorylation is mediated by cyclin C-dependent kinases, as shown by coimmunoprecipitation of LSF and cyclin C in early G(1) and by abrogation of LSF S309 phosphorylation upon suppression of cyclin C with short interfering RNA. Although mouse fibroblasts lack functional CDK3 (the partner of cyclin C in early G(1) in human cells), CDK2 compensates for this absence. By transient transfection assays, phosphorylation at S309, mediated by cyclin C overexpression, inhibits LSF transactivation. Moreover, overexpression of cyclin C and CDK3 inhibits induction of endogenous Tyms expression at the G(1)/S transition. These results identify LSF as only the second known target (in addition to pRb) of cyclin C/CDK activity during progression from quiescence to early G(1). Unexpectedly, this phosphorylation prevents induction of LSF target genes until late G(1).