21 September 2006<br>
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Rivoglitazone<br>
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A Randomized, Double-Blind, Placebo- and Active Comparator- Controlled, Parallel-Group Study of the Efficacy and Safety of Rivoglitazone as Monotherapy Treatment of Type 2 Diabetes Mellitus<br>
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Sponsor:   Daiichi Sankyo Pharma Development (DSPD)<br>
Study Drug: CS-011 aka Rivoglitazone<br>  
Protocol: CS0011-A-U301<br> 	 
Phase 3<br>
CRO: Medpace<br>
CRA: <br>
Medical Monitor:   John Isacson<br> 
Site #:<br>  
Central Lab: PPDi<br>
IRB:  IntegReview http://www.integreview.com/ <br>   
Subjects / 250 Sites -> 5 Subjects per Site R in 5 groups in a 1:2:2:2:2 ratio of:<br> 
Placebo: Rivoglitazone @ 1.0: 1.5: 2.0: Actos 45<br> 
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PPARs are transcription factors belonging to the superfamily of nuclear receptors that modulate the transcription of genes responsible for numerous cellular processes.  PPAR ? regulates the expression of genes involved in lipid and glucose homeostasis.<br>
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20 September 2006<br>
VERSION:  1 2 3 4 5 6 7 8 9<br>
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Rivoglitazone<br>
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 IC<br>
18-75<br>
HbA1C 7 – 9.5<br> 
BMI: equal/greater than 23 AND equal/less than 45<br>
Non-fasting C-peptide > 0.5<br>
3 Month h/o:  non-TZD Monotherapy or 2 Months Diet Controlled NIDDM<br>
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EC<br>
BP >180/110<br>
CHF III or IV<br>
Insulin or TZD Use<br>
BMI > 40<br>
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20 September 2006<br>
VERSION:  1 2 3 4 5 6 7 8 9<br>
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Rivoglitazone<br>
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V1   W -3	Lab, Screening Visit<br>
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V2   W -2	Lab, d/c DM Meds, Single-Blind Placebo lead-in, CXR, Echo, EKG <br>
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V2P W -1   Phone Contact to review FBSs<br> 
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V3   W 0	Lab, EKG,  R  Double-Blind Treatment Period B<br>
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V4   W 2	Lab, Glycemic Control Evaluation for possible Glucophage addition<br> 
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V5   W 4	Lab<br>
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V6  W 6	Lab<br>
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V7  W 8    Lab<br>
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V8  W 10   Lab<br>
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V9  W 12  Lab, EKG<br>
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V10  W 16  Lab<br>
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V11  W 18  Lab<br>
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V12  W 20  Lab<br>
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V 13 W 22  Lab<br>
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V 14 W 24  Lab<br>
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V 16 W26   Lab, EKG, ET<br>
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V17 W 28 Lab, Period C F/U Visit for subjects not electing to do long term extension trial<br>
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PPARs<br>
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Peroxisome Proliferator-activated Receptors (PPARs) are nuclear receptors involved in lipid and glucose homeostasis, inflammation and wound healing.<br>
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Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors belonging to the superfamily of nuclear receptors that modulate the transcription of genes responsible for regulating lipid and lipoprotein metabolism, glucose homeostasis and inflammation along with numerous other cellular processes.<br>
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The PPAR family consists of three proteins:<br>
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1.	Alpha<br>
2.	Beta/Delta<br>
3.	Gamma<br>
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Recent data suggest that PPAR alpha and gamma activation decreases atherosclerosis progression not only by correcting metabolic disorders, but also through direct effects on the vascular wall. <br>
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The peroxisome proliferator-activated receptors (PPARs) play central roles in lipid and glucose homeostasis, cellular differentiation, and the immune/inflammatory response.<br>
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PPARs modulate the recruitment of leukocytes to endothelial cells, control the inflammatory response and lipid homeostasis of monocytes/macrophages and regulate inflammatory cytokine production by smooth muscle cells.<br>
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In addition to ligand binding, phosphorylation can regulate PPARs; the biological effects of phosphorylation depend on the stimulus, the kinase, the PPAR isotype, the residue modified, the cell type and the promoter investigated.<br>
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