14 CLINICAL STUDIES

14.1 Monotherapy

In a 24-week, double-blind, placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide tablets (60 mg or 120 mg three times daily before meals) or placebo. Patients previously treated with antidiabetic medications were required to discontinue that medication for at least 2 months before randomization.

At Week 24, treatment with nateglinide tablets before meals resulted in statistically significant reductions in mean HbA1C and mean fasting plasma glucose (FPG) compared to placebo (see Table 5). The reductions in HbA1C and FPG were similar for patient's naive to, and those previously exposed to, antidiabetic medications.

Table 5: Endpoint Results for a 24-week, Fixed Dose Study of Nateglinide Monotherapy

	Placebo	Nateglinide Tablets 60 mg three times daily before meals	Nateglinide Tablets 120 mg three times daily before meals
p-value≤0.004
HbA1C (%)	N=168	N=167	N=168
Baseline (mean)	8.0	7.9	8.1
Change from baseline (mean)	+0.2	-0.3	-0.5
Difference from placebo (mean)		-0.5*	-0.7*
FPG (mg/dL)	N=172	N=171	N=169
Baseline (mean)	167.9	161.0	166.5
Change from baseline (mean)	+9.1	+0.4	-4.5
Difference from placebo (mean)		-8.7 *	-13.6 *

14.2 Monotherapy Compared to Glyburide

In a 24-week, double-blind, active-controlled trial, patients with type 2 diabetes who had been on a sulfonylurea for 3 or more months and who had a baseline HbA 1 C greater than or equal to 6.5% were randomized to receive nateglinide tablets (60 mg or 120 mg three times daily before meals) or glyburide 10 mg once daily. Patients randomized to nateglinide tablets had statistically significant increases in mean HbA1C and mean FPG at endpoint compared to patients randomized to glyburide.

Table 6: Endpoint Results for a 24-week Study of Nateglinide Monotherapy Compared to Glyburide

	Glyburide 10 mg Once daily	Nateglinide 60 mg three times daily before meals	Nateglinide 120 mg three times daily before meals
p-value <0.001
HbA1C (%)	N=183	N=178	N=179
Baseline (mean)	7.8	8.0	7.9
Change from baseline (mean)	0.3	1.3	1.1
Difference from glyburide		1.0*	0.9*
FPG(mmol/L)	N=184	N=182	N=180
Baseline (mean)	9.44	9.67	9.61
Change from baseline (mean)	0.19	3.06	2.84
Difference from glyburide		2.87*	2.66*

14.3 Monotherapy and In Combination With Metformin

In a 24-week, double-blind, active- and placebo-controlled study, patients with type 2 diabetes were randomized to receive either nateglinide alone (120 mg three times daily before meals), metformin alone (500 mg three times daily), a combination of nateglinide tablets 120 mg (three times daily before meals) and metformin (500 mg three times daily), or placebo. Fifty-seven percent of patients were previously untreated with oral antidiabetic therapy. Patients previously treated with antidiabetic medications were required to discontinue medication for at least 2 months before randomization.

At Week 24, statistically significant reductions in mean HbA1c and FPG were observed with metformin monotherapy compared to nateglinide tablets monotherapy, and the combination of nateglinide tablets and metformin compared to either nateglinide tablets or metformin monotherapy (see Table 7).

Compared to placebo, nateglinide monotherapy was associated with a statistically significant increase in mean body weight, while no significant change in body weight was observed with metformin monotherapy or combination of nateglinide and metformin therapy (see Table 7). Among the subset of patients previously treated with other antidiabetic agents, primarily glyburide, HbA1C in the nateglinide monotherapy group increased slightly from baseline, whereas HbA1C was reduced in the metformin monotherapy group (see Table 7).

Table 7: Endpoint results for a 24-week study of Nateglinide Monotherapy and Combination with Metformin

	Placebo	Nateglinide 120 mg three times daily	Metformin 500 mg three times daily	Nateglinide 120 mg before meals plus Metformin*
Metformin was administered three times daily † p-value≤0.03 vs. metformin ‡ p-value≤0.05 vs. combination § p-value≤0.05 vs. placebo
HbA1C(%) All	N=160	N=171	N=172	N=162
Baseline (mean)	8.3	8.3	8.4	8.4
Change from baseline (mean)	+0.4	-0.4†‡	-0.8‡	-1.5
Difference from placebo		-0.8§	-1.2§	-1.9§
Naïve	N=98	N=99	N=98	N=81
Baseline (mean)	8.2	8.1	8.3	8.2
Change from baseline (mean)	+0.3	-0.7‡	-0.8‡	-1.6
Difference from placebo		-1.0§	-1.1§	-1.9§
Non-Naïve	N=62	N=72	N=74	N=81
Baseline (mean)	8.3	8.5	8.7	8.7
Change from baseline (mean)	+0.6	+0.004†‡	-0.8‡	-1.4
Difference from placebo		-0.6§	-1.4a	-2.0§
FPG (mg/dL)
All	N=166	N=173	N=174	N=167
Baseline (mean)	194.0	196.5	196.0	197.7
Change from baseline (mean)	+8.0	-13.1†‡	-30.0‡	-44.9
Difference from placebo		-21.1§	-38.0§	-52.9§

In another 24-week, double-blind, placebo-controlled trial, patients with type 2 diabetes with HbA1C greater than or equal to 6.8% after treatment with metformin (greater than or equal to 1,500 mg daily for at least 1 month) were first entered into a four week run-in period of metformin monotherapy (2,000 mg daily) and then randomized to receive either nateglinide tablets (60 mg or 120 mg three limes daily before meals) or placebo as add-on to metformin. At the end of treatment, nateglinide tablets 60 mg and 120 mg three times daily resulted in a statistically significantly greater reductions in HbA1C compared to placebo when added to metformin (-0.4% and -0.6% for nateglinide tablets 60 mg and nateglinide tablets 120 mg plus metformin, respectively).

Table 8: Endpoint Results for a 24-week Study of Nateglinide Monotherapy as Add-on to Metformin

	Placebo + 006Detformin	Nateglinide 60 mg + metformin	Nateglinide 120 mg + metformin
HbA1C (%)	N=150	N=152	N=154
p-value 0.003 vs. metformin † p-value < 0.001 vs. metformin All nateglinide /placebo taken three times daily before meals; all metformin 1,000 mg twice daily.
Baseline (mean)	8.2	8.0	8.2
Change from baseline (mean)	0.01	-0.4	-0.6
Difference from metformin		-0.4*	-0.6†

14.4 Add-On Combination Therapy With Rosiglitazone

A 24-week, double blind, multicenter, placebo-controlled trial was performed in patients with type 2 diabetes not adequately controlled on rosiglitazone 8 mg daily. The addition of nateglinide (120 mg three times per day with meals) was associated with statistically significantly greater reductions in HbA1C compared to placebo as add-on to rosiglitazone. The mean change in weight from baseline was +3 kg for patients treated with nateglinide tablets compared to +1 kg for patients treated with placebo when added to rosiglitazone.

Table 9: Endpoint Results for a 24-week Study of the Effect of Adding Nategllnlde or Placebo to Rosiglitazone

	Placebo + roalglitazone 8 mg once daily	Nateglinide 120 mg before meals + rosiglitazone 8 mg once daily
HbA1C (%)	N=191	N=194
p-value≤0.0001
Baseline (mean)	8.4	8.3
Change from baseline (mean)	0.03	-0.7
Difference from rosiglitazone (mean)		-0.7*

14.5 Add-On Combination Therapy With Glyburide

In a 12-week study of patients with type 2 diabetes inadequately controlled on glyburide 10 mg once daily, the addition of nateglinide (60 mg or 120 mg three times daily before meals) did not produce any additional benefit.

Table 10: Endpoint Results for a 12-week Study of the Effect of Adding Nateglinide or Placebo to Glyburide

	Placebo + roalglitazone 8 mg once daily	Nateglinide 120 mg before meals + rosiglitazone 8 mg once daily
HbA1C (%)	N=191	N=194
p-value≤0.0001
Baseline (mean)	8.4	8.3
Change from baseline (mean)	0.03	-0.7
Difference from rosiglitazone (mean)		-0.7*