Diabetes phase 3 studies

Prevention of vascular disease is one of the goals of a study in progress in Sweden, in which newly diagnosed diabetic children have been randomized in a doubleblind study where one group receives placebo and the other a preparation containing ascorbic acid, )3-carotene, nicotinamide, selenium and vitamin E (Ludvigsson, 1992). Future research with antioxidants may attempt to prevent the onset of pancreatic beta-cell destruction in the prediabetic phase of susceptible individuals. 

Currently, there are a number of systemic and intestine-selective MTP inhibitors, including lomitapide (23, BMS-201038, AEGR-733), implitapide (24), JTT-130, SLx-4090, and R-256918 (latter three structures not disclosed) believed to be in active development [60]. In a meta-analysis of three Phase II clinical trials, lomitapide as monotherapy or in combination with ezetimibe, atorvastatin, or fenofibrate significantly reduced LDL cholesterol (up to 35% as monotherapy and 66% in combination with atorvastatin) and was well tolerated with less than 2% discontinuation due to abnormal liver function [61]. Lomitapide has also been granted orphan drug status for the treatment of homozygous familial hypercholesterolemia [59]. Results of a Phase II study of JTT-130 for type 2 diabetes are expected in August 2010 [59,60]. 

Fibrates are being combined with statins to expand their potential in the dyslipidemia market. A recent clinical study examined the effects of rosuvastatin (10) and fenofibrate as mono and combination therapy in hyperlipidemic diabetic patients [43]. In late 2006, large scale Phase III clinical trials of rosuvastatin in combination with a next-generation fibrate, ABT 335, were initiated for evaluation of safety and efficacy in patients with mixed dyslipidemia. 

Insulin-dependent posttransplant diabetes mellitus (PTDMj. lnsulin-dependent PTDM was reported in 20% of tacrolimus-treated kidney patients without pretransplant history of diabetes mellitus in the Phase 3 study. The median time to onset of PTDM was 68 days. Insulin dependence was reversible in 15% of these PTDM patients at 1 year and in 50% at 2 years posttransplant. Black and Hispanic kidney transplant patients were at an increased risk of development of PTDM. 

One of the main drivers for the development of new pulmonary drug delivery systems has been the potential for noninvasive systemic delivery of protein and peptide compounds. The systemic delivery of macromolecules via the airways would overcome the inconvenience and cost associated with current methods of administration (injection), and appears likely given the large surface area of the airways and the thin pulmonary epithelium. Most research has concentrated on pulmonary delivery of insulin for the treatment of diabetes. Recently, one insulin product has completed phase three studies and is now undergoing review by European regulatory agencies for marketing approval. 

Of 210 patients with type 2 diabetes, 179 completed a randomized study of the effects of five different doses (0.045, 0.225, 0.45, 0.6, and 0.75 mg) or metformin 100 mg bd for 12 weeks after a 4-week metformin run-in phase. The numbers of people who reported nausea and vomiting were small (4%) and comparable to the incidence with metformin (6%) (15). Careful upwards titration allows higher doses (2 mg/day) to be tolerated (2). 

Lavezzari M, Milanesi G, Oggioni E, Pamparana F. Results of a phase IV study carried out with acipimox in type II diabetic patients with concomitant hyperlipoproteinaemia. J Int Med Res 1989 17(4) 373-80. 

Quattrin, T., Belanger, A., Bohannon, N. J., Schwartz, S. L., and Exubera Phase III Study Group (2004), Efficacy and safety of inhaled insulin (exubera) compared with subcutaneous insulin therapy in patients with type 1 diabetes Results of a 6-month, randomized, comparative trial, Diabetes Care, 27,2622-2627. 

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