###  Monotherapy

In the U.S., three randomized, double-blind, placebo-controlled trials with durations from 16 to 26 weeks were conducted to evaluate the use of ACTOS as monotherapy in patients with type 2 diabetes. These studies examined ACTOS at doses up to 45 mg or placebo once daily in 865 patients. 

In a 26-week, dose-ranging study, 408 patients with type 2 diabetes were randomized to receive 7.5 mg, 15 mg, 30 mg, or 45 mg of ACTOS, or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 8 weeks prior to the double-blind period. Treatment with 15 mg, 30 mg, and 45 mg of ACTOS produced statistically significant improvements in HbA1c and fasting plasma glucose (FPG) at endpoint compared to placebo (Figure 1, Table 2).

Figure 1 shows the time course for changes in FPG and HbA1c for the entire study population in this 26-week study. 

Figure 1 Mean Change from Baseline for FPG and HbA1c in a 26-Week Placebo-  
Controlled Dose-Ranging Study

Table 2 shows HbA1c and FPG values for the entire study population.

The study population included patients not previously treated with antidiabetic medication (naïve; 31%) and patients who were receiving antidiabetic medication at the time of study enrollment (previously treated; 69%). The data for the naïve and previously-treated patient subsets are shown in Table 3. All patients entered an 8 week washout/run-in period prior to double-blind treatment. This run-in period was associated with little change in HbA1c and FPG values from screening to baseline for the naïve patients; however, for the previously-treated group, washout from previous antidiabetic medication resulted in deterioration of glycemic control and increases in HbA1c and FPG. Although most patients in the previously-treated group had a decrease from baseline in HbA1c and FPG with ACTOS, in many cases the values did not return to screening levels by the end of the study. The study design did not permit the evaluation of patients who switched directly to ACTOS from another antidiabetic agent.

In a 24-week, placebo-controlled study, 260 patients with type 2 diabetes were randomized to one of two forced-titration ACTOS treatment groups or a mock titration placebo group. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. In one ACTOS treatment group, patients received an initial dose of 7.5 mg once daily. After four weeks, the dose was increased to 15 mg once daily and after another four weeks, the dose was increased to 30 mg once daily for the remainder of the study (16 weeks). In the second ACTOS treatment group, patients received an initial dose of 15 mg once daily and were titrated to 30 mg once daily and 45 mg once daily in a similar manner. Treatment with ACTOS, as described, produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (Table 4).

For patients who had not been previously treated with antidiabetic medication (24%), mean values at screening were 10.1% for HbA1c and 238 mg/dL for FPG. At baseline, mean HbA1c was 10.2% and mean FPG was 243 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 2.3% and 2.6% and mean FPG of 63 mg/dL and 95 mg/dL, respectively. For patients who had been previously treated with antidiabetic medication (76%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FPG. At baseline, mean HbA1c was 10.7% and mean FPG was 290 mg/dL. Compared with placebo, treatment with ACTOS titrated to a final dose of 30 mg and 45 mg resulted in reductions from baseline in mean HbA1c of 1.3% and 1.4% and mean FPG of 55 mg/dL and 60 mg/dL, respectively. For many previously-treated patients, HbA1c and FPG had not returned to screening levels by the end of the study. 

In a 16-week study, 197 patients with type 2 diabetes were randomized to treatment with 30 mg of ACTOS or placebo once daily. Therapy with any previous antidiabetic agent was discontinued 6 weeks prior to the double-blind period. Treatment with 30 mg of ACTOS produced statistically significant improvements in HbA1c and FPG at endpoint compared to placebo (Table 5).

For patients who had not been previously treated with antidiabetic medication (40%), mean values at screening were 10.3% for HbA1c and 240 mg/dL for FPG. At baseline, mean HbA1c was 10.4% and mean FPG was 254 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.0% and mean FPG of 62 mg/dL. For patients who had been previously treated with antidiabetic medication (60%), this medication was discontinued at screening. Mean values at screening were 9.4% for HbA1c and 216 mg/dL for FPG. At baseline, mean HbA1c was 10.6% and mean FPG was 287 mg/dL. Compared with placebo, treatment with ACTOS 30 mg resulted in reductions from baseline in mean HbA1c of 1.3% and mean FPG of 46 mg/dL. For many previously-treated patients, HbA1c and FPG had not returned to screening levels by the end of the study.

###  Combination Therapy

Three 16-week, randomized, double-blind, placebo-controlled clinical studies and three 24-week, randomized, double-blind, dose-controlled clinical studies were conducted to evaluate the effects of ACTOS on glycemic control in patients with type 2 diabetes who were inadequately controlled (HbA1c ≥ 8%) despite current therapy with a sulfonylurea, metformin, or insulin. Previous diabetes treatment may have been monotherapy or combination therapy.

####  ACTOS Plus Sulfonylurea Studies

Two clinical studies were conducted with ACTOS in combination with a sulfonylurea. Both studies included patients with type 2 diabetes on a sulfonylurea, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 560 patients were randomized to receive 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current sulfonylurea regimen. When compared to placebo at Week 16, the addition of ACTOS to the sulfonylurea significantly reduced the mean HbA1c by 0.9% and 1.3% and mean FPG by 39 mg/dL and 58 mg/dL for the 15 mg and 30 mg doses, respectively. 

In the second study, 702 patients were randomized to receive 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current sulfonylurea regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.55% and 1.67% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 51.5 mg/dL and 56.1 mg/dL.

The therapeutic effect of ACTOS in combination with sulfonylurea was observed in patients regardless of whether the patients were receiving low, medium, or high doses of sulfonylurea.

####  ACTOS Plus Metformin Studies

Two clinical studies were conducted with ACTOS in combination with metformin. Both studies included patients with type 2 diabetes on metformin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 328 patients were randomized to receive either 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their current metformin regimen. When compared to placebo at Week 16, the addition of ACTOS to metformin significantly reduced the mean HbA1c by 0.8% and decreased the mean FPG by 38 mg/dL. 

In the second study, 827 patients were randomized to receive either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current metformin regimen. The mean reductions from baseline at Week 24 in HbA1c were 0.80% and 1.01% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 38.2 mg/dL and 50.7 mg/dL.

The therapeutic effect of ACTOS in combination with metformin was observed in patients regardless of whether the patients were receiving lower or higher doses of metformin.

####  ACTOS Plus Insulin Studies

Two clinical studies were conducted with ACTOS in combination with insulin. Both studies included patients with type 2 diabetes on insulin, either alone or in combination with another antidiabetic agent. All other antidiabetic agents were withdrawn prior to starting study treatment. In the first study, 566 patients receiving a median of 60.5 units per day of insulin were randomized to receive either 15 mg or 30 mg of ACTOS or placebo once daily for 16 weeks in addition to their insulin regimen. When compared to placebo at Week 16, the addition of ACTOS to insulin significantly reduced both HbA1c by 0.7% and 1.0% and FPG by 35 mg/dL and 49 mg/dL for the 15 mg and 30 mg dose, respectively. 

In the second study, 690 patients receiving a median of 60.0 units per day of insulin received either 30 mg or 45 mg of ACTOS once daily for 24 weeks in addition to their current insulin regimen. The mean reductions from baseline at Week 24 in HbA1c were 1.17% and 1.46% for the 30 mg and 45 mg doses, respectively. Mean reductions from baseline in FPG were 31.9 mg/dL and 45.8 mg/dL. Improved glycemic control was accompanied by mean decreases from baseline in insulin dose requirements of 6.0% and 9.4% per day for the 30 mg and 45 mg dose, respectively.

The therapeutic effect of ACTOS in combination with insulin was observed in patients regardless of whether the patients were receiving lower or higher doses of insulin.