NIDDM-HTN
Beyond Atacand

A Phase III, Double-Blind, Randomized, Placebo-Controlled Study to Determine the Efficacy, Safety and Tolerability of AD-4833-536 in the Treatment of Subjects with Type 2 Diabetes and Hypertension

Sponsor: TGRD (Takeda Global Research & Development Center, Inc)
Study Drug: AD-4833-536 (Actos + TAK-536)
Protocol: SYR-320PI-002
Phase III
CRO: ICON
CRA:
Medical Monitor:
Site #:
Central Lab:
IRB:
900 Subjects / 150 Sites -> 6 Subjects per Site R in 6 groups in a 1:1:1:1:1:1 ratio of
a) Actos 30 + Placebo
b) Actos 30 + 20 AD-4833-536
c) Actos 30 + 40 AD-4833-536
d) Actos 45 + Placebo
e) Actos 45 + 20 AD-4833-536
f) Actos 45 + 40 AD-4833-536

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NIDDM-HTN
Beyond Atacand

The Science

TAK-536 is a novel ARB that modulates the RAS (Renin-Angiotensin-Aldosterone) System. It is similar to Atacand but has weight loss associated with it!

TAK-536 with Actos causes:
a) BP reduction
b) Weight Loss
c) improved TG
d) improved Sugar

Two receptors for AII (Angiotensin II) have been identified:
1. Angiotensin II type 1 (AT1) receptors which are found in vascular smooth muscle & cause: Vasoconstriction; Hypertrophic Proliferation; and, Inflammation.
2. Angiotensin II type 2 (AT2) receptors cause: Vasodilatation; Anti-Proliferate effects; and other effects that are opposite to those of AT1 stimulation.

ACE Inhibitors block the synthesis of AII by inhibiting Angiotensin Converting Enzyme.

ARBs (Angiotensin Receptor Blockers) inhibit the action of AII by binding directly to the AT1 receptor resulting in arterial vasodilatation and BP reduction.

Actos (Pioglitazone) is a PPAR gamma/TZD. PPARs are transcription factors belonging to the superfamily of nuclear receptors that modulate the transcription of genes responsible for numerous cellular processes. PPAR’s regulate the expression of genes involved in lipid and glucose homeostasis.

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NIDDM-HTN
Beyond Atacand

IC
Age equal/more than 18
HbA1C at Screening equal/more than 8.0 to equal/less than 10.5
DBP at Randomization equal/more than 90 and equal/less than 109
BMI: equal/less than 45
Stable NIDDM (diet, exercise & drug) x 8 wks prior to screening

EC
BP > 180/109 at Randomization or after wk 6 > 160/90
TZD or Insulin within 12 wks prior to screening
Niacin
NSAIDs or Steroids
CHF Class III or IV or being treated for CHF
LFT > 2.5 times ULN
Any h/o: CAD, MI, CVA, TIA, PTCA, AF, LBBB
CRF: Creatinine > 2.0. If on Glucophage: Men Creatinine equal/more than 1.5 Women Creatinine equal/more than 1.4
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NIDDM-HTN
Beyond Atacand

V1 D -21 Lab, Screening, ICF, EKG, D/C BP Meds, +/- 3 D

V2 D -7 Lab, Washout, RTC Window +/- 2 Days

V3 D 1 Lab, Randomization , Call IVRS

V4 W 2 Lab, Treatment Phase, RTC Window +/- 2 Days

V5 W 6 Lab, Rescue Norvasc if needed, RTC Window +/- 3 Days

V6 W 12 Lab, Rescue Norvasc if needed, RTC Window +/- 3 Days

V7 W 18 Lab, Rescue Norvasc if needed, RTC Window +/- 3 Days

V8 W 24 Lab, Early Termination, EKG

PPARs

Peroxisome Proliferator-activated Receptors (PPARs) are nuclear receptors involved in lipid and glucose homeostasis, inflammation and wound healing.

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.

The PPAR family consists of three proteins:
1. Alpha
2. Beta/Delta
3. Gamma
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.

The peroxisome proliferator-activated receptors (PPARs) play central roles in lipid and glucose homeostasis, cellular differentiation, and the immune/inflammatory response.

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.

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.