INVOKANA (Page 6 of 9)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Carcinogenicity was evaluated in 2-year studies conducted in CD1 mice and Sprague-Dawley rats. Canagliflozin did not increase the incidence of tumors in mice dosed at 10, 30, or 100 mg/kg (less than or equal to 14 times exposure from a 300 mg clinical dose).

Testicular Leydig cell tumors, considered secondary to increased luteinizing hormone (LH), increased significantly in male rats at all doses tested (10, 30, and 100 mg/kg). In a 12-week clinical trial, LH did not increase in males treated with canagliflozin.

Renal tubular adenoma and carcinoma increased significantly in male and female rats dosed at 100 mg/kg, or approximately 12-times exposure from a 300 mg clinical dose. Also, adrenal pheochromocytoma increased significantly in males and numerically in females dosed at 100 mg/kg. Carbohydrate malabsorption associated with high doses of canagliflozin was considered a necessary proximal event in the emergence of renal and adrenal tumors in rats. Clinical trials have not demonstrated carbohydrate malabsorption in humans at canagliflozin doses of up to 2-times the recommended clinical dose of 300 mg.

Mutagenesis

Canagliflozin was not mutagenic with or without metabolic activation in the Ames assay. Canagliflozin was mutagenic in the in vitro mouse lymphoma assay with but not without metabolic activation. Canagliflozin was not mutagenic or clastogenic in an in vivo oral micronucleus assay in rats and an in vivo oral Comet assay in rats.

Impairment of Fertility

Canagliflozin had no effects on the ability of rats to mate and sire or maintain a litter up to the high dose of 100 mg/kg (approximately 14 times and 18 times the 300 mg clinical dose in males and females, respectively), although there were minor alterations in a number of reproductive parameters (decreased sperm velocity, increased number of abnormal sperm, slightly fewer corpora lutea, fewer implantation sites, and smaller litter sizes) at the highest dosage administered.

14 CLINICAL STUDIES

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

INVOKANA (canagliflozin) has been studied as monotherapy, in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and sitagliptin, metformin and a thiazolidinedione (i.e., pioglitazone), and in combination with insulin (with or without other anti-hyperglycemic agents). The efficacy of INVOKANA was compared to a dipeptidyl peptidase-4 (DPP-4) inhibitor (sitagliptin), both as add-on combination therapy with metformin and sulfonylurea, and a sulfonylurea (glimepiride), both as add-on combination therapy with metformin. INVOKANA was also evaluated in adults 55 to 80 years of age and patients with moderate renal impairment.

Monotherapy

A total of 584 patients with type 2 diabetes inadequately controlled on diet and exercise participated in a 26-week double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA. The mean age was 55 years, 44% of patients were men, and the mean baseline eGFR was 87 mL/min/1.73 m2. Patients taking other antihyperglycemic agents (N=281) discontinued the agent and underwent an 8-week washout followed by a 2-week, single-blind, placebo run-in period. Patients not taking oral antihyperglycemic agents (N=303) entered the 2-week, single-blind, placebo run-in period directly. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily for 26 weeks.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo (see Table 9). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -3.7 mmHg and -5.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 9:Results from 26-Week Placebo-Controlled Clinical Study with INVOKANA as Monotherapy *
Efficacy Parameter Placebo (N=192) INVOKANA 100 mg (N=195) INVOKANA 300 mg (N=197)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001

HbA1C (%)

Baseline (mean)

7.97

8.06

8.01

Change from baseline (adjusted mean)

0.14

-0.77

-1.03

Difference from placebo (adjusted mean) (95% CI)

-0.91(-1.09; -0.73)

-1.16(-1.34; -0.99)

Percent of Patients Achieving HbA1C < 7%

21

45

62

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

166

172

173

Change from baseline (adjusted mean)

8

-27

-35

Difference from placebo (adjusted mean) (95% CI)

-36(-42; -29)

-43(-50; -37)

2-hour Postprandial Glucose (mg/dL)

Baseline (mean)

229

250

254

Change from baseline (adjusted mean)

5

-43

-59

Difference from placebo (adjusted mean) (95% CI)

-48(-59.1; -37.0)

-64(-75.0; -52.9)

Body Weight

Baseline (mean) in kg

87.5

85.9

86.9

% change from baseline (adjusted mean)

-0.6

-2.8

-3.9

Difference from placebo (adjusted mean) (95% CI)

-2.2(-2.9; -1.6)

-3.3(-4.0; -2.6)

Add-on Combination Therapy with Metformin

A total of 1,284 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 26-week, double-blind, placebo- and active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin. The mean age was 55 years, 47% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the required metformin dose (N=1009) were randomized after completing a 2-week, single-blind, placebo run-in period. Patients taking less than the required metformin dose or patients on metformin in combination with another antihyperglycemic agent (N=275) were switched to metformin monotherapy (at doses described above) for at least 8 weeks before entering the 2-week, single-blind, placebo run-in. After the placebo run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, sitagliptin 100 mg, or placebo, administered once daily as add-on therapy to metformin.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG), in improved postprandial glucose (PPG), and in percent body weight reduction compared to placebo when added to metformin (see Table 10). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -5.4 mmHg and -6.6 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 10: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin *
Efficacy Parameter Placebo + Metformin (N=183) INVOKANA 100 mg + Metformin (N=368) INVOKANA 300 mg + Metformin (N=367)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001

HbA1C (%)

Baseline (mean)

7.96

7.94

7.95

Change from baseline (adjusted mean)

-0.17

-0.79

-0.94

Difference from placebo (adjusted mean) (95% CI)

-0.62(-0.76; -0.48)

-0.77(-0.91; -0.64)

Percent of patients achieving HbA1C < 7%

30

46

58

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

164

169

173

Change from baseline (adjusted mean)

2

-27

-38

Difference from placebo (adjusted mean) (95% CI)

-30(-36; -24)

-40(-46; -34)

2-hour Postprandial Glucose (mg/dL)

Baseline (mean)

249

258

262

Change from baseline (adjusted mean)

-10

-48

-57

Difference from placebo (adjusted mean) (95% CI)

-38(-49; -27)

-47(-58; -36)

Body Weight

Baseline (mean) in kg

86.7

88.7

85.4

% change from baseline (adjusted mean)

-1.2

-3.7

-4.2

Difference from placebo (adjusted mean) (95% CI)

-2.5(-3.1; -1.9)

-2.9(-3.5; -2.3)

Initial Combination Therapy with Metformin

A total of 1,186 patients with type 2 diabetes inadequately controlled with diet and exercise participated in a 26-week double-blind, active-controlled, parallel-group, 5-arm, multicenter trial to evaluate the efficacy and safety of initial therapy with INVOKANA in combination with metformin XR. The median age was 56 years, 48% of patients were men, and the mean baseline eGFR was 87.6 mL/min/1.73 m2. The median duration of diabetes was 1.6 years, and 72% of patients were treatment naïve. After completing a 2-week single-blind placebo run-in period, patients were randomly assigned for a double-blind treatment period of 26 weeks to 1 of 5 treatment groups (Table 11). The metformin XR dose was initiated at 500 mg/day for the first week of treatment and then increased to 1000 mg/day. Metformin XR or matching placebo was up-titrated every 2–3 weeks during the next 8 weeks of treatment to a maximum daily dose of 1500 to 2000 mg/day, as tolerated; about 90% of patients reached 2000 mg/day.

At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg in combination with metformin XR resulted in a statistically significant greater improvement in HbA1C compared to their respective INVOKANA doses (100 mg and 300 mg) alone or metformin XR alone.

Table 11: Results from 26-Week Active-Controlled Clinical Study of INVOKANA Alone or INVOKANA as Initial Combination Therapy with Metformin *
Efficacy Parameter Metformin XR (N=237) INVOKANA 100 mg (N=237) INVOKANA 300 mg (N=238) INVOKANA 100 mg + Metformin XR (N=237) INVOKANA 300 mg + Metformin XR (N=237)
*
Intent-to-treat population
There were 121 patients without week 26 efficacy data. Analyses addressing missing data gave consistent results with the results provided in this table.
Least squares mean adjusted for covariates including baseline value and stratification factor
§
Adjusted p=0.001 for superiority
Adjusted p=0.001 for non-inferiority
#
Adjusted p<0.05

HbA1C (%)

Baseline (mean)

8.81

8.78

8.77

8.83

8.90

Change from baseline (adjusted mean)

-1.30

-1.37

-1.42

-1.77

-1.78

Difference from canagliflozin 100 mg (adjusted mean) (95% CI)

-0.40§(-0.59, -0.21)

Difference from canagliflozin 300 mg (adjusted mean) (95% CI)

-0.36§(-0.56, -0.17)

Difference from metformin XR (adjusted mean) (95% CI)

-0.06(-0.26, 0.13)

-0.11(-0.31, 0.08)

-0.46§(-0.66, -0.27)

-0.48§(-0.67, -0.28)

Percent of patients achieving HbA1C < 7%

38

34

39

47#

51#

INVOKANA Compared to Glimepiride, Both as Add-on Combination With Metformin

A total of 1,450 patients with type 2 diabetes inadequately controlled on metformin monotherapy (greater than or equal to 2,000 mg/day, or at least 1,500 mg/day if higher dose not tolerated) participated in a 52-week, double-blind, active-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin.

The mean age was 56 years, 52% of patients were men, and the mean baseline eGFR was 90 mL/min/1.73 m2. Patients tolerating maximally required metformin dose (N=928) were randomized after completing a 2-week, single-blind, placebo run-in period. Other patients (N=522) were switched to metformin monotherapy (at doses described above) for at least 10 weeks, then completed a 2-week single-blind run-in period. After the 2-week run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or glimepiride (titration allowed throughout the 52-week trial to 6 or 8 mg), administered once daily as add-on therapy to metformin.

As shown in Table 12 and Figure 1, at the end of treatment, INVOKANA 100 mg provided similar reductions in HbA1C from baseline compared to glimepiride when added to metformin therapy. INVOKANA 300 mg provided a greater reduction from baseline in HbA1C compared to glimepiride, and the relative treatment difference was -0.12% (95% CI: –0.22; –0.02). As shown in Table 12, treatment with INVOKANA 100 mg and 300 mg daily provided greater improvements in percent body weight change, relative to glimepiride.

Table 12: Results from 52–Week Clinical Study Comparing INVOKANA to Glimepiride in Combination with Metformin *
Efficacy Parameter INVOKANA 100 mg + Metformin (N=483) INVOKANA 300 mg + Metformin (N=485) Glimepiride (titrated) + Metformin (N=482)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
INVOKANA + metformin is considered non-inferior to glimepiride + metformin because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§
p<0.001

HbA1C (%)

Baseline (mean)

7.78

7.79

7.83

Change from baseline (adjusted mean)

-0.82

-0.93

-0.81

Difference from glimepiride (adjusted mean) (95% CI)

-0.01(-0.11; 0.09)

-0.12(-0.22; -0.02)

Percent of patients achieving HbA1C < 7%

54

60

56

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

165

164

166

Change from baseline (adjusted mean)

-24

-28

-18

Difference from glimepiride (adjusted mean) (95% CI)

-6(-10; -2)

-9(-13; -5)

Body Weight

Baseline (mean) in kg

86.8

86.6

86.6

% change from baseline (adjusted mean)

-4.2

-4.7

1.0

Difference from glimepiride (adjusted mean) (95% CI)

-5.2§(-5.7; -4.7)

-5.7§(-6.2; -5.1)

Figure 1: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)
Figure 1
(click image for full-size original)

Add-on Combination Therapy with Sulfonylurea

A total of 127 patients with type 2 diabetes inadequately controlled on sulfonylurea monotherapy participated in an 18-week, double-blind, placebo-controlled sub-study to evaluate the efficacy and safety of INVOKANA in combination with sulfonylurea. The mean age was 65 years, 57% of patients were men, and the mean baseline eGFR was 69 mL/min/1.73 m2. Patients treated with sulfonylurea monotherapy on a stable protocol-specified dose (greater than or equal to 50% maximal dose) for at least 10 weeks completed a 2-week, single-blind, placebo run-in period. After the run-in period, patients with inadequate glycemic control were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to sulfonylurea.

As shown in Table 13, at the end of treatment, INVOKANA 100 mg and 300 mg daily provided statistically significant (p<0.001 for both doses) improvements in HbA1C relative to placebo when added to sulfonylurea. INVOKANA 300 mg once daily compared to placebo resulted in a greater proportion of patients achieving an HbA1C less than 7%, (33% vs 5%), greater reductions in fasting plasma glucose (-36 mg/dL vs +12 mg/dL), and greater percent body weight reduction (-2.0% vs -0.2%).

Table 13: Results from 18-Week Placebo–Controlled Clinical Study of INVOKANA in Combination with Sulfonylurea *
Efficacy Parameter Placebo + Sulfonylurea (N=45) INVOKANA 100 mg + Sulfonylurea (N=42) INVOKANA 300 mg + Sulfonylurea (N=40)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value
p<0.001

HbA1C (%)

Baseline (mean)

8.49

8.29

8.28

Change from baseline (adjusted mean)

0.04

-0.70

-0.79

Difference from placebo (adjusted mean) (95% CI)

-0.74(-1.15; -0.33)

-0.83(-1.24; -0.41)

Add-on Combination Therapy with Metformin and Sulfonylurea

A total of 469 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (maximal or near-maximal effective dose) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin and sulfonylurea. The mean age was 57 years, 51% of patients were men, and the mean baseline eGFR was 89 mL/min/1.73 m2. Patients already on the protocol-specified doses of metformin and sulfonylurea (N=372) entered a 2-week, single-blind, placebo run-in period. Other patients (N=97) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and sulfonylurea.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and sulfonylurea. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in a significant reduction in fasting plasma glucose (FPG), and in percent body weight reduction compared to placebo when added to metformin and sulfonylurea (see Table 14).

Table 14: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Sulfonylurea *
Efficacy Parameter Placebo + Metformin and Sulfonylurea (N=156) INVOKANA 100 mg + Metformin and Sulfonylurea (N=157) INVOKANA 300 mg + Metformin and Sulfonylurea (N=156)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001

HbA1C (%)

Baseline (mean)

8.12

8.13

8.13

Change from baseline (adjusted mean)

-0.13

-0.85

-1.06

Difference from placebo (adjusted mean) (95% CI)

-0.71(-0.90; -0.52)

-0.92(-1.11; -0.73)

Percent of patients achieving A1C < 7%

18

43

57

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

170

173

168

Change from baseline (adjusted mean)

4

-18

-31

Difference from placebo (adjusted mean) (95% CI)

-22(-31; -13)

-35(-44; -25)

Body Weight

Baseline (mean) in kg

90.8

93.5

93.5

% change from baseline (adjusted mean)

-0.7

-2.1

-2.6

Difference from placebo (adjusted mean) (95% CI)

-1.4(-2.1; -0.7)

-2.0(-2.7; -1.3)

Add-on Combination Therapy with Metformin and Sitagliptin

A total of 217 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 1,500 mg/day) and sitagliptin 100 mg/day (or equivalent fixed-dose combination) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin and sitagliptin. The mean age was 57 years, 58% of patients were men, 73% of patients were Caucasian, 15% were Asian, and 12% were Black or African-American. The mean baseline eGFR was 90 mL/min/1.73 m2 and the mean baseline BMI was 32 kg/m2. The mean duration of diabetes was 10 years. Eligible patients entered a 2-week, single-blind, placebo run-in period and were subsequently randomized to INVOKANA 100 mg or placebo, administered once daily as add-on to metformin and sitagliptin. Patients with a baseline eGFR of 70 mL/min/1.73 m2 or greater who were tolerating INVOKANA 100 mg and who required additional glycemic control (fasting finger stick 100 mg/dL or greater at least twice within 2 weeks) were up-titrated to INVOKANA 300 mg. While up-titration occurred as early as Week 4, most (90%) patients randomized to INVOKANA were up-titrated to INVOKANA 300 mg by 6 to 8 weeks.

At the end of 26 weeks, INVOKANA resulted in a statistically significant improvement in HbA1C (p<0.001) compared to placebo when added to metformin and sitagliptin.

Table 15: Results from 26–Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Sitagliptin
Efficacy Parameter Placebo + Metformin and Sitagliptin (N=108 * ) INVOKANA + Metformin and Sitagliptin (N=109 * )
*
To preserve the integrity of randomization, all randomized patients were included in the analysis. The patient who was randomized once to each arm was analyzed on INVOKANA.
Early treatment discontinuation before week 26, occurred in 11.0% and 24.1% of INVOKANA and placebo patients, respectively.
Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. Missing data was imputed only at week 26 and analyzed using ANCOVA.
§
p<0.001
Patients without week 26 efficacy data were considered as non-responders when estimating the proportion achieving HbA1c < 7%.
#
Estimated using a multiple imputation method modeling a “wash-out” of the treatment effect for patients having missing data who discontinued treatment. A mixed model for repeated measures was used to analyze the imputed data.

HbA1C (%)

Baseline (mean)

8.40

8.50

Change from baseline (adjusted mean)

-0.03

-0.83

Difference from placebo (adjusted mean) (95% CI)

-0.81§(-1.11; -0.51)

Percent of patients achieving HbA1C < 7%

9

28

Fasting Plasma Glucose (mg/dL) #

Baseline (mean)

180

185

Change from baseline (adjusted mean)

-3

-28

Difference from placebo (adjusted mean) (95% CI)

-25§(-39; -11)

INVOKANA Compared to Sitagliptin, Both as Add-on Combination Therapy with Metformin and Sulfonylurea

A total of 755 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and sulfonylurea (near-maximal or maximal effective dose) participated in a 52-week, double-blind, active-controlled trial to compare the efficacy and safety of INVOKANA 300 mg versus sitagliptin 100 mg in combination with metformin and sulfonylurea. The mean age was 57 years, 56% of patients were men, and the mean baseline eGFR was 88 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin and sulfonylurea (N=716) entered a 2-week single-blind, placebo run-in period. Other patients (N=39) were required to be on a stable protocol-specified dose of metformin and sulfonylurea for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 300 mg or sitagliptin 100 mg as add-on to metformin and sulfonylurea.

As shown in Table 16 and Figure 2, at the end of treatment, INVOKANA 300 mg provided greater HbA1C reduction compared to sitagliptin 100 mg when added to metformin and sulfonylurea (p<0.05). INVOKANA 300 mg resulted in a mean percent change in body weight from baseline of -2.5% compared to +0.3% with sitagliptin 100 mg. A mean change in systolic blood pressure from baseline of -5.06 mmHg was observed with INVOKANA 300 mg compared to +0.85 mmHg with sitagliptin 100 mg.

Table 16: Results from 52-Week Clinical Study Comparing INVOKANA to Sitagliptin in Combination with Metformin and Sulfonylurea *
Efficacy Parameter INVOKANA 300 mg + Metformin and Sulfonylurea (N=377) Sitagliptin 100 mg + Metformin and Sulfonylurea (N=378)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
INVOKANA + metformin + sulfonylurea is considered non-inferior to sitagliptin + metformin + sulfonylurea because the upper limit of this confidence interval is less than the pre-specified non-inferiority margin of < 0.3%.
§
p<0.001

HbA1C (%)

Baseline (mean)

8.12

8.13

Change from baseline (adjusted mean)

-1.03

-0.66

Difference from sitagliptin (adjusted mean) (95% CI)

-0.37(-0.50; -0.25)

Percent of patients achieving HbA1C < 7%

48

35

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

170

164

Change from baseline (adjusted mean)

-30

-6

Difference from sitagliptin (adjusted mean) (95% CI)

-24(-30; -18)

Body Weight

Baseline (mean) in kg

87.6

89.6

% change from baseline (adjusted mean)

-2.5

0.3

Difference from sitagliptin (adjusted mean) (95% CI)

-2.8§(-3.3; -2.2)

Figure 2: Mean HbA1C Change at Each Time Point (Completers) and at Week 52 Using Last Observation Carried Forward (mITT Population)

Figure 2
(click image for full-size original)

Add-on Combination Therapy with Metformin and Pioglitazone

A total of 342 patients with type 2 diabetes inadequately controlled on the combination of metformin (greater than or equal to 2,000 mg/day or at least 1,500 mg/day if higher dose not tolerated) and pioglitazone (30 or 45 mg/day) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with metformin and pioglitazone. The mean age was 57 years, 63% of patients were men, and the mean baseline eGFR was 86 mL/min/1.73 m2. Patients already on protocol-specified doses of metformin and pioglitazone (N=163) entered a 2-week, single-blind, placebo run-in period. Other patients (N=181) were required to be on stable protocol-specified doses of metformin and pioglitazone for at least 8 weeks before entering the 2-week run-in period. Following the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to metformin and pioglitazone.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to metformin and pioglitazone. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reduction in fasting plasma glucose (FPG) and in percent body weight reduction compared to placebo when added to metformin and pioglitazone (see Table 17). Statistically significant (p<0.05 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -4.1 mmHg and -3.5 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 17: Results from 26-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Metformin and Pioglitazone *
Efficacy Parameter Placebo + Metformin and Pioglitazone (N=115) INVOKANA 100 mg + Metformin and Pioglitazone (N=113) INVOKANA 300 mg + Metformin and Pioglitazone (N=114)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001

HbA1C (%)

Baseline (mean)

8.00

7.99

7.84

Change from baseline (adjusted mean)

-0.26

-0.89

-1.03

Difference from placebo (adjusted mean) (95% CI)

-0.62(-0.81; -0.44)

-0.76(-0.95; -0.58)

Percent of patients achieving HbA1C < 7%

33

47

64

Fasting Plasma Glucose (mg/dL)

Baseline (mean)

164

169

164

Change from baseline (adjusted mean)

3

-27

-33

Difference from placebo (adjusted mean) (95% CI)

-29(-37; -22)

-36(-43; -28)

Body Weight

Baseline (mean) in kg

94.0

94.2

94.4

% change from baseline (adjusted mean)

-0.1

-2.8

-3.8

Difference from placebo (adjusted mean) (95% CI)

-2.7(-3.6; -1.8)

-3.7(-4.6; -2.8)

Add-On Combination Therapy with Insulin (With or Without Other Antihyperglycemic Agents)

A total of 1,718 patients with type 2 diabetes inadequately controlled on insulin greater than or equal to 30 units/day or insulin in combination with other antihyperglycemic agents participated in an 18-week, double-blind, placebo-controlled substudy of a cardiovascular trial to evaluate the efficacy and safety of INVOKANA in combination with insulin. The mean age was 63 years, 66% of patients were men, and the mean baseline eGFR was 75 mL/min/1.73 m2. Patients on basal, bolus, or basal/bolus insulin for at least 10 weeks entered a 2-week, single-blind, placebo run-in period. Approximately 70% of patients were on a background basal/bolus insulin regimen. After the run-in period, patients were randomized to INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily as add-on to insulin. The mean daily insulin dose at baseline was 83 units, which was similar across treatment groups.

At the end of treatment, INVOKANA 100 mg and 300 mg once daily resulted in a statistically significant improvement in HbA1C (p<0.001 for both doses) compared to placebo when added to insulin. INVOKANA 100 mg and 300 mg once daily also resulted in a greater proportion of patients achieving an HbA1C less than 7%, in significant reductions in fasting plasma glucose (FPG), and in percent body weight reductions compared to placebo (see Table 18). Statistically significant (p<0.001 for both doses) mean changes from baseline in systolic blood pressure relative to placebo were -2.6 mmHg and -4.4 mmHg with INVOKANA 100 mg and 300 mg, respectively.

Table 18: Results from 18-Week Placebo-Controlled Clinical Study of INVOKANA in Combination with Insulin ≥ 30 Units/Day (With or Without Other Oral Antihyperglycemic Agents)*
Efficacy Parameter Placebo + Insulin (N=565) INVOKANA 100 mg + Insulin (N=566) INVOKANA 300 mg + Insulin (N=587)
*
Intent-to-treat population using last observation in study prior to glycemic rescue therapy
Least squares mean adjusted for baseline value and stratification factors
p<0.001

HbA1C (%)

Baseline (mean)

8.20

8.33

8.27

Change from baseline (adjusted mean)

0.01

-0.63

-0.72

Difference from placebo (adjusted mean) (95% CI)

-0.65(-0.73; -0.56)

-0.73(-0.82; -0.65)

Percent of patients achieving HbA1C < 7%

8

20

25

Fasting Plasma Glucose (mg/dL)

Baseline

169

170

168

Change from baseline (adjusted mean)

4

-19

-25

Difference from placebo (adjusted mean) (97.5% CI)

-23(-29; -16)

-29(-35; -23)

Body Weight

Baseline (mean) in kg

97.7

96.9

96.7

% change from baseline (adjusted mean)

0.1

-1.8

-2.3

Difference from placebo (adjusted mean) (97.5% CI)

-1.9(-2.2; -1.6)

-2.4(-2.7; -2.1)

Study in Patients Ages 55 to 80

A total of 714 type 2 diabetes patients ages 55 to 80 years and inadequately controlled on current diabetes therapy (either diet and exercise alone or in combination with oral or parenteral agents) participated in a 26-week, double-blind, placebo-controlled trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment. The mean age was 64 years, 55% of patients were men, and the mean baseline eGFR was 77 mL/min/1.73 m2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily. At the end of treatment, INVOKANA provided statistically significant improvements from baseline relative to placebo in HbA1C (p<0.001 for both doses) of -0.57% (95% CI: -0.71%; -0.44%) for INVOKANA 100 mg and -0.70% (95% CI: -0.84%; -0.57%) for INVOKANA 300 mg. [see Use in Specific Populations (8.5)].

Glycemic Control in Patients with Moderate Renal Impairment

A total of 269 patients with type 2 diabetes and a baseline eGFR of 30 mL/min/1.73 m2 to less than 50 mL/min/1.73 m2 inadequately controlled on current diabetes therapy participated in a 26-week, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of INVOKANA in combination with current diabetes treatment (diet or antihyperglycemic agent therapy, with 95% of patients on insulin and/or sulfonylurea). The mean age was 68 years, 61% of patients were men, and the mean baseline eGFR was 39 mL/min/1.73 m2. Patients were randomized in a 1:1:1 ratio to the addition of INVOKANA 100 mg, INVOKANA 300 mg, or placebo, administered once daily.

At the end of treatment, INVOKANA 100 mg and INVOKANA 300 mg daily provided greater reductions in HbA1C relative to placebo (-0.30% [95% CI: -0.53%; -0.07%] and -0.40%, [95% CI: -0.64%; -0.17%], respectively) [see Warnings and Precautions (5.2), Adverse Reactions (6.1), Use in Specific Populations (8.6), and Clinical Studies (14.3)].

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