DSI: Joseph Saponaro

SPhD 011-203
Rivoglitazone

A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, 26-Week Dose-Response Study of Rivoglitazone (CS-011) with Active Comparator (Pioglitazone/Actos) in Subjects with Type 2 Diabetes

Sponsor: Sankyo Pharma Development (SPhD)
Study Drug: CS-011
Protocol: CS-011-203 Phase 2b
Study Manager: Norma Roebker, Medpace, Inc. N.Roebker@Medpace.com
CRO: Medpace, Inc.
Medical Monitor: Jonathan Isaacsohn, MD
Site/Investigator #: 090
CRA: Michelle Cecic -> M.Cecic@Medpace.com or 513-289-8325
Study Drug: Rivoglitazone -> PPARy
Central Lab: MRLi
Last day to enroll subjects: May 2005
Central IRB = Quorum IRB
425 Subjects/ 80 Sites = 6 Subjects per Site
Five Treatment Groups of Drug: 1:1:1:1:1 -> Rivoglitazone 1: 2: 3: Actos 45mgm: Placebo (85 x 5 = 425)
IVRS: Dynarand
Central EKG Lab -> eResearch Technology
SAE Hotline: 800-730-5779 x 2999
Serious Adverse Event Report Form (SAVER) Fax: 513-579-0444
Genotyping to analyze genes involved in the safety and efficacy of Rivoglitazone
B-type Natriuretic Peptide (BNP) -> CHF

Resistin: A small protein (114 amino acids) secreted by mice fat cells that's an adipocyte-derived cytokine which causes insulin resistance by causing tissues (esp. liver) to be less sensitive to the actions of insulin and results in glucose intolerance in mice by resisting insulin. www.phoenixpeptide.com/Catalog%20Files/Resistin/resistin.htm

Adiponectin: A protein hormone produced and secreted exclusively by adipocytes (fat cells) that regulates the metabolism of lipids and glucose. Adiponectin influences the body's response to insulin. Adiponectin also has anti-inflammatory effects on the cells lining the walls of blood vessels. High blood levels of adiponectin are associated with a reduced risk of heart attack. Low levels of adiponectin are found in people who are obese (and who are at increased risk of a heart attack).

IC
Men Age: 18 – 75 or Women Not of Child Bearing Potential (tubes tied, TAH or BSO or post menopausal x 1 year)
HbA1C ? 7.0 and < 10.5 & FPG ? 250 & C-Peptide > 0.5 @ V1 W-1
Medically justifiable to withdraw anti-diabetic Rx x 16 wks
NIDDM on: Diet, SU, Glucophage or Glyset -> No PPARy's

EC
Insulin; Hypoglycemia or Lactic Acidosis x 6 months; h/o fructose intolerance; BMI ? 45; Proteinuria; DMPN; DM Retinopathy; Diabetic micro-/macro-angiopathy, BP > 160/95; CHF (3 or 4); 6 Months h/o: MI, Unstable Angina, CVA, TIA; h/o TZD use ever!
Hematuria, Hepatitis B or C, CA x 10 yrs, 160/95, FSG < 60 or > 260
Con Meds -> Prednisone, Digoxin, Coumadin, Theo., anti-Sz meds, Tagamet, anti-arrhythmics, Barbiturates, Phenothiazines, TZD

V 1 W -1 Lab, Screening, ICF, IVRS, CXR, VS, BMI D/C DM Meds day before V2
V 2 W 0 Lab, Randomization, CPE, EKG x 3, VS, IVRS (Interactive Voice Recognition System)
(Note that the study medication diary was dispensed)
V 3 W 1 Lab, Visit Window +/- 3 Days, Study Medication Diary to record date & time
V 4 W 2 Lab, Study Drug will be 3 Tabs & 1 Cap taken q AM
V 5 W 3 Lab Record the date & time of the last meal & the time of the lab draw
V 6 W 4 Lab, VS (Vital Signs)
V 7 W 6 Lab, If FPG > 220, repeat in 3 D, If still high -> Flunk Out
V 8 W 8 Lab, VS Note that they brought study drug with them to the office & took it after the blood draw
V 9 W 10 Lab
V10 W 12 Lab, VS, If FPG > 200, repeat in 3 D, If still high -> Flunk Out
V11 W 14 Lab
V12 W 16 Lab, VS
V13 W 18 Lab
V14 W 20 Lab, VS, If FPG > 180, repeat in 3 D, If still high -> Flunk Out
V15 W 22 Lab
V16 W 24 Lab
V17 W 26 Lab, VS, IVRS, EKG, CPE (Complete Physical Exam)

Record the Date & Time of the last meal & the time the Blood was Drawn as there is a required 10H fast.
Note that the subject didn’t take the study drug the morning they come in.
Note that the subject brought the study drug with them & consumed it here in our office.

Michelle Cecic came to monitor the study & had some requests:

HT to be written on the Medication Sheet
BMI to be done on V1
Record the Source of the Referral
For all Fasting V's -> They need to fast at least 10h. Record the date & time of the last meal & the time the blood was drawn.
V2 ? Note study med diary dispensed
Note that they didn't take study drug the morning they come in & that they brought the study drug with them & consumed it here in our office.
If woman has TAH -> Record reason they had it.
Our Radio Ad does not have the tape aural copy. We have to ask Anna Thomas for a copy of the ad that ran on the radio.