药物信息为ONGLYZA (saxagliptin) tablets Initial U.S. Approval: 2009 (E.R. Squibb & Sons, L.L.C.): 14 CLINICAL STUDIES

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  • ONGLYZA has been studied as monotherapy and in combination with metformin, glyburide, and thiazolidinedione (pioglitazone and rosiglitazone) therapy. ONGLYZA has not been studied in combination with insulin.

    A total of 4148 patients with type 2 diabetes mellitus were randomized in six, double-blind, controlled clinical trials conducted to evaluate the safety and glycemic efficacy of ONGLYZA. A total of 3021 patients in these trials were treated with ONGLYZA. In these trials, the mean age was 54 years, and 71% of patients were Caucasian, 16% were Asian, 4% were black, and 9% were of other racial groups. An additional 423 patients, including 315 who received ONGLYZA, participated in a placebo-controlled, dose-ranging study of 6 to 12 weeks in duration.

    In these six, double-blind trials, ONGLYZA was evaluated at doses of 2.5 mg and 5 mg once daily. Three of these trials also evaluated a saxagliptin dose of 10 mg daily. The 10 mg daily dose of saxagliptin did not provide greater efficacy than the 5 mg daily dose. Treatment with ONGLYZA at all doses produced clinically relevant and statistically significant improvements in hemoglobin A1c (A1C), fasting plasma glucose (FPG), and 2-hour postprandial glucose (PPG) following a standard oral glucose tolerance test (OGTT), compared to control. Reductions in A1C were seen across subgroups including gender, age, race, and baseline BMI.

    ONGLYZA was not associated with significant changes from baseline in body weight or fasting serum lipids compared to placebo.

  • 14.1 Monotherapy

  • A total of 766 patients with type 2 diabetes inadequately controlled on diet and exercise (A1C =7% to =10%) participated in two 24-week, double-blind, placebo-controlled trials evaluating the efficacy and safety of ONGLYZA monotherapy.

    In the first trial, following a 2-week single-blind diet, exercise, and placebo lead-in period, 401 patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy, added on to placebo or ONGLYZA. Efficacy was evaluated at the last measurement prior to rescue therapy for patients needing rescue. Dose titration of ONGLYZA was not permitted.

    Treatment with ONGLYZA 2.5 mg and 5 mg daily provided significant improvements in A1C, FPG, and PPG compared to placebo (Table 3). The percentage of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 16% in the ONGLYZA 2.5 mg treatment group, 20% in the ONGLYZA 5 mg treatment group, and 26% in the placebo group.

  • Table 3: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA Monotherapy in Patients with Type 2 Diabetes*
    Efficacy ParameterONGLYZA2.5 mgN=102ONGLYZA5 mgN=106PlaceboN=95
    * Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.
    Least squares mean adjusted for baseline value.
    p-value <0.0001 compared to placebo
    § p-value <0.05 compared to placebo
    Significance was not tested for the 2-hour PPG for the 2.5 mg dose of ONGLYZA.
    Hemoglobin A1C (%)N=100N=103N=92
    Baseline (mean)7.98.07.9
    Change from baseline (adjusted mean)-0.4-0.5+0.2
    Difference from placebo (adjusted mean)-0.6-0.6
    95% Confidence Interval(-0.9, -0.3)(-0.9, -0.4)
    Percent of patients achieving A1C <7%35% (35/100)38%§ (39/103)24% (22/92)
    Fasting Plasma Glucose (mg/dL)N=101N=105N=92
    Baseline (mean)178171172
    Change from baseline (adjusted mean)-15-9+6
    Difference from placebo (adjusted mean)-21§-15§
    95% Confidence Interval(-31, -10)(-25, -4)
    2-hour Postprandial Glucose (mg/dL)N=78N=84N=71
    Baseline (mean)279278283
    Change from baseline (adjusted mean)-45-43-6
    Difference from placebo (adjusted mean)-39-37§
    95% Confidence Interval(-61, -16)(-59, -15)
  • A second 24-week monotherapy trial was conducted to assess a range of dosing regimens for ONGLYZA. Treatment-naive patients with inadequately controlled diabetes (A1C =7% to =10%) underwent a 2-week, single-blind diet, exercise, and placebo lead-in period. A total of 365 patients were randomized to 2.5 mg every morning, 5 mg every morning, 2.5 mg with possible titration to 5 mg every morning, or 5 mg every evening of ONGLYZA, or placebo. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue therapy added on to placebo or ONGLYZA; the number of patients randomized per treatment group ranged from 71 to 74.

    Treatment with either ONGLYZA 5 mg every morning or 5 mg every evening provided significant improvements in A1C versus placebo (mean placebo-corrected reductions of -0.4% and -0.3%, respectively). Treatment with ONGLYZA 2.5 mg every morning also provided significant improvement in A1C versus placebo (mean placebo-corrected reduction of -0.4%).

  • Add-On Combination Therapy with Metformin

  • A total of 743 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with metformin in patients with inadequate glycemic control (A1C =7% and =10%) on metformin alone. To qualify for enrollment, patients were required to be on a stable dose of metformin (1500-2550 mg daily) for at least 8 weeks.

    Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received metformin at their pre-study dose, up to 2500 mg daily, for the duration of the study. Following the lead-in period, eligible patients were randomized to 2.5 mg, 5 mg, or 10 mg of ONGLYZA or placebo in addition to their current dose of open-label metformin. Patients who failed to meet specific glycemic goals during the study were treated with pioglitazone rescue therapy, added on to existing study medications. Dose titrations of ONGLYZA and metformin were not permitted.

    ONGLYZA 2.5 mg and 5 mg add-on to meformin provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to metformin (Table 4). Mean changes from baseline for A1C over time and at endpoint are shown in Figure 1. The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 15% in the ONGLYZA 2.5 mg add-on to metformin group, 13% in the ONGLYZA 5 mg add-on to metformin group, and 27% in the placebo add-on to metformin group.

    Table 4: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with Metformin*
    Efficacy ParameterONGLYZA 2.5 mg+MetforminN=192ONGLYZA 5 mg+MetforminN=191Placebo+MetforminN=179
    * Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.
    Least squares mean adjusted for baseline value.
    p-value <0.0001 compared to placebo + metformin
    § p-value <0.05 compared to placebo + metformin
    Hemoglobin A1C (%)N=186N=186N=175
    Baseline (mean)8.18.18.1
    Change from baseline (adjusted mean)-0.6-0.7+0.1
    Difference from placebo (adjusted mean)-0.7-0.8
    95% Confidence Interval(-0.9, -0.5)(-1.0, -0.6)
    Percent of patients achieving A1C <7%37%§ (69/186)44%§ (81/186)17% (29/175)
    Fasting Plasma Glucose (mg/dL)N=188N=187N=176
    Baseline (mean)174179175
    Change from baseline (adjusted mean)-14-22+1
    Difference from placebo (adjusted mean)-16§-23§
    95% Confidence Interval(-23, -9)(-30, -16)
    2-hour Postprandial Glucose (mg/dL)N=155N=155N=135
    Baseline (mean)294296295
    Change from baseline (adjusted mean)-62-58-18
    Difference from placebo (adjusted mean)-44§-40§
    95% Confidence Interval(-60, -27)(-56, -24)
    Figure 1: Mean Change from Baseline in A1C in a Placebo-Controlled Trial of ONGLYZA as Add-On Combination Therapy with Metformin*
    * Includes patients with a baseline and week 24 value.Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.
  • Add-On Combination Therapy with a Thiazolidinedione

  • A total of 565 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a thiazolidinedione (TZD) in patients with inadequate glycemic control (A1C =7% to =10.5%) on TZD alone. To qualify for enrollment, patients were required to be on a stable dose of pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks.

    Patients who met eligibility criteria were enrolled in a single-blind, 2-week, dietary and exercise placebo lead-in period during which patients received TZD at their pre-study dose for the duration of the study. Following the lead-in period, eligible patients were randomized to 2.5 mg or 5 mg of ONGLYZA or placebo in addition to their current dose of TZD. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medications. Dose titration of ONGLYZA or TZD was not permitted during the study. A change in TZD regimen from rosiglitazone to pioglitazone at specified, equivalent therapeutic doses was permitted at the investigator’s discretion if believed to be medically appropriate.

    ONGLYZA 2.5 mg and 5 mg add-on to TZD provided significant improvements in A1C, FPG, and PPG compared with placebo add-on to TZD (Table 5). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 10% in the ONGLYZA 2.5 mg add-on to TZD group, 6% for the ONGLYZA 5 mg add-on to TZD group, and 10% in the placebo add-on to TZD group.

    Table 5: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with a Thiazolidinedione*
    Efficacy ParameterONGLYZA 2.5 mg+TZDN=195ONGLYZA 5 mg+TZDN=186Placebo+TZDN=184
    * Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.
    Least squares mean adjusted for baseline value.
    p-value <0.0001 compared to placebo + TZD
    § p-value <0.05 compared to placebo + TZD
    Hemoglobin A1C (%)N=192N=183N=180
    Baseline (mean)8.38.48.2
    Change from baseline (adjusted mean)-0.7-0.9-0.3
    Difference from placebo (adjusted mean)-0.4§-0.6
    95% Confidence Interval(-0.6, -0.2)(-0.8, -0.4)
    Percent of patients achieving A1C <7%42%§ (81/192)42%§ (77/184)26% (46/180)
    Fasting Plasma Glucose (mg/dL)N=193N=185N=181
    Baseline (mean)163160162
    Change from baseline (adjusted mean)-14-17-3
    Difference from placebo (adjusted mean)-12§-15§
    95% Confidence Interval(-20, -3)(-23, -6)
    2-hour Postprandial Glucose (mg/dL)N=156N=134N=127
    Baseline (mean)296303291
    Change from baseline (adjusted mean)-55-65-15
    Difference from placebo (adjusted mean)-40§-50§
    95% Confidence Interval(-56, -24)(-66, -34)
  • Add-On Combination Therapy with Glyburide

  • A total of 768 patients with type 2 diabetes participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA in combination with a sulfonylurea (SU) in patients with inadequate glycemic control at enrollment (A1C =7.5% to =10%) on a submaximal dose of SU alone. To qualify for enrollment, patients were required to be on a submaximal dose of SU for 2 months or greater. In this study, ONGLYZA in combination with a fixed, intermediate dose of SU was compared to titration to a higher dose of SU.

    Patients who met eligibility criteria were enrolled in a single-blind, 4-week, dietary and exercise lead-in period, and placed on glyburide 7.5 mg once daily. Following the lead-in period, eligible patients with A1C =7% to =10% were randomized to either 2.5 mg or 5 mg of ONGLYZA add-on to 7.5 mg glyburide or to placebo plus a 10 mg total daily dose of glyburide. Patients who received placebo were eligible to have glyburide up-titrated to a total daily dose of 15 mg. Up-titration of glyburide was not permitted in patients who received ONGLYZA 2.5 mg or 5 mg. Glyburide could be down-titrated in any treatment group once during the 24-week study period due to hypoglycemia as deemed necessary by the investigator. Approximately 92% of patients in the placebo plus glyburide group were up-titrated to a final total daily dose of 15 mg during the first 4 weeks of the study period. Patients who failed to meet specific glycemic goals during the study were treated with metformin rescue, added on to existing study medication. Dose titration of ONGLYZA was not permitted during the study.

    In combination with glyburide, ONGLYZA 2.5 mg and 5 mg provided significant improvements in A1C, FPG, and PPG compared with the placebo plus up-titrated glyburide group (Table 6). The proportion of patients who discontinued for lack of glycemic control or who were rescued for meeting prespecified glycemic criteria was 18% in the ONGLYZA 2.5 mg add-on to glyburide group, 17% in the ONGLYZA 5 mg add-on to glyburide group, and 30% in the placebo plus up-titrated glyburide group.

    Table 6: Glycemic Parameters at Week 24 in a Placebo-Controlled Study of ONGLYZA as Add-On Combination Therapy with Glyburide*
    Efficacy ParameterONGLYZA2.5 mg+ Glyburide7.5 mgN=248ONGLYZA5 mg+ Glyburide7.5 mgN=253Placebo+ Up-Titrated GlyburideN=267
    * Intent-to-treat population using last observation on study or last observation prior to metformin rescue therapy for patients needing rescue.
    Least squares mean adjusted for baseline value.
    p-value <0.0001 compared to placebo + up-titrated glyburide
    § p-value <0.05 compared to placebo + up-titrated glyburide
    Hemoglobin A1C (%)N=246N=250N=264
    Baseline (mean)8.48.58.4
    Change from baseline (adjusted mean)-0.5-0.6+0.1
    Difference from up-titrated glyburide (adjusted mean)-0.6-0.7
    95% Confidence Interval(-0.8, -0.5)(-0.9, -0.6)
    Percent of patients achieving A1C <7%22%§ (55/246)23%§ (57/250)9% (24/264)
    Fasting Plasma Glucose (mg/dL)N=247N=252N=265
    Baseline (mean)170175174
    Change from baseline (adjusted mean)-7-10+1
    Difference from up-titrated glyburide (adjusted mean)-8§-10§
    95% Confidence Interval(-14, -1)(-17, -4)
    2-hour Postprandial Glucose (mg/dL)N=195N=202N=206
    Baseline (mean)309315323
    Change from baseline (adjusted mean)-31-34+8
    Difference from up-titrated glyburide (adjusted mean)-38§-42§
    95% Confidence Interval(-50, -27)(-53, -31)
  • Coadministration with Metformin in Treatment-Naive Patients

  • A total of 1306 treatment-naive patients with type 2 diabetes mellitus participated in this 24-week, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of ONGLYZA coadministered with metformin in patients with inadequate glycemic control (A1C =8% to =12%) on diet and exercise alone. Patients were required to be treatment-naive to be enrolled in this study.

    Patients who met eligibility criteria were enrolled in a single-blind, 1-week, dietary and exercise placebo lead-in period. Patients were randomized to one of four treatment arms: ONGLYZA 5 mg + metformin 500 mg, saxagliptin 10 mg + metformin 500 mg, saxagliptin 10 mg + placebo, or metformin 500 mg + placebo. ONGLYZA was dosed once daily. In the 3 treatment groups using metformin, the metformin dose was up-titrated weekly in 500 mg per day increments, as tolerated, to a maximum of 2000 mg per day based on FPG. Patients who failed to meet specific glycemic goals during the studies were treated with pioglitazone rescue as add-on therapy.

    Coadministration of ONGLYZA 5 mg plus metformin provided significant improvements in A1C, FPG, and PPG compared with placebo plus metformin (Table 7).

    Table 7: Glycemic Parameters at Week 24 in a Placebo-Controlled Trial of ONGLYZA Coadministration with Metformin in Treatment-Naive Patients*
    Efficacy ParameterONGLYZA 5 mg+ MetforminN=320Placebo+MetforminN=328
    * Intent-to-treat population using last observation on study or last observation prior to pioglitazone rescue therapy for patients needing rescue.
    Least squares mean adjusted for baseline value.
    p-value <0.0001 compared to placebo + metformin
    § p-value <0.05 compared to placebo + metformin
    Hemoglobin A1C (%)N=306N=313
    Baseline (mean)9.49.4
    Change from baseline (adjusted mean)-2.5-2.0
    Difference from placebo + metformin (adjusted mean)-0.5
    95% Confidence Interval(-0.7, -0.4)
    Percent of patients achieving A1C <7%60%§ (185/307)41% (129/314)
    Fasting Plasma Glucose (mg/dL)N=315N=320
    Baseline (mean)199199
    Change from baseline (adjusted mean)-60-47
    Difference from placebo + metformin (adjusted mean)-13§
    95% Confidence Interval(-19, -6)
    2-hour Postprandial Glucose (mg/dL)N=146N=141
    Baseline (mean)340355
    Change from baseline (adjusted mean)-138-97
    Difference from placebo + metformin (adjusted mean)-41§
    95% Confidence Interval(-57, -25)
  • Drug Information Provided by National Library of Medicine (NLM).
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