Safety and tolerability of canagliflozin in patients with type 2 diabetes mellitus: pooled analysis of phase 3 study results.

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Safety and Tolerability of Canagliflozin in Patients With Type 2 Diabetes Mellitus: Pooled Analysis of Phase 3 Study Results a

b

c

d

Keith Usiskin MD , Irina Kline MD , Albert Fung BS , Cristiana Mayer PhD & Gary Meininger MD

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Senior Director and Clinical Leader, Janssen Research & Development, LLC, Raritan, NJ

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Director of Metabolism, Janssen Research & Development, LLC, Raritan, NJ

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Associate Director and Clinical Project Scientist, Janssen Research & Development, LLC, Raritan, NJ d

Scientific Director, Statistical Modeling MBDD, Janssen Research & Development, LLC, Titusville, NJ e

Vice President, Franchise Medical Leader–Metabolism, Janssen Research & Development, LLC, Raritan, NJ Published online: 28 May 2015.

To cite this article: Keith Usiskin MD, Irina Kline MD, Albert Fung BS, Cristiana Mayer PhD & Gary Meininger MD (2014) Safety and Tolerability of Canagliflozin in Patients With Type 2 Diabetes Mellitus: Pooled Analysis of Phase 3 Study Results, Postgraduate Medicine, 126:3, 16-34 To link to this article: http://dx.doi.org/10.3810/pgm.2014.05.2753

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C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S

Safety and Tolerability of Canagliflozin in Patients With Type 2 Diabetes Mellitus: Pooled Analysis of Phase 3 Study Results

Downloaded by [University of Otago] at 19:09 21 July 2015

DOI: 10.3810/pgm.2014.05.2753

Keith Usiskin, MD 1 Irina Kline, MD 2 Albert Fung, BS 3 Cristiana Mayer, PhD 4 Gary Meininger, MD 5 1 Senior Director and Clinical Leader, Janssen Research & Development, LLC, Raritan, NJ; 2Director of Metabolism, Janssen Research & Development, LLC, Raritan, NJ; 3 Associate Director and Clinical Project Scientist, Janssen Research & Development, LLC, Raritan, NJ; 4 Scientific Director, Statistical Modeling MBDD, Janssen Research & Development, LLC, Titusville, NJ; 5 Vice President, Franchise Medical Leader–Metabolism, Janssen Research & Development, LLC, Raritan, NJ

Abstract

Background: Canagliflozin is a sodium glucose cotransporter 2 inhibitor developed for treating type 2 diabetes mellitus (T2DM). Methods: The safety/tolerability profile of canagliflozin 100 and 300 mg over 26 weeks was assessed using an integrated analysis of data pooled from 4 placebo-controlled, phase 3 studies representing a broad range of patients with T2DM (N = 2313; mean age, 56.0 years; glycated hemoglobin [HbA1c], 8.0%; body mass index, 32.1 kg/m2; estimated glomerular filtration rate, 88.1 mL/min/1.73 m2) on various prespecified background diabetes mellitus treatments. Safety/tolerability evaluations included adverse event (AE) reporting, with additional data collection prespecified for selected AEs, and assessments of renal-related, lipid, and other safety laboratory parameters. Trial Registration: ClinicalTrials.gov, NCT01081834; NCT01106625; NCT01106677; NCT01106690. Results: The overall incidence of AEs was similar with canagliflozin 100 and 300 mg and placebo; incidences of serious AEs and AEs leading to study discontinuation were low across groups. Canagliflozin was associated with higher incidences than placebo of genital mycotic infections and osmotic diuresis–related AEs; these were generally considered by the investigator to be mild to moderate in intensity and infrequently led to discontinuation. Canagliflozin was associated with transient reductions in estimated glomerular filtration rate that trended toward baseline over the assessment period; incidences of renal-related AEs were low across groups. Dose-related increases in the incidence of hypoglycemia episodes were seen with canagliflozin versus placebo in patients on background sulfonylurea; incidences of severe hypoglycemia were low across groups. Hypoglycemia incidence was low overall in patients not on background sulfonylurea, but slightly higher with canagliflozin versus placebo. Relative to placebo, favorable changes in high-density lipoprotein cholesterol and triglycerides were seen with canagliflozin; increases in low-density lipoprotein cholesterol were also seen. Canagliflozin was associated with small changes in other safety laboratory parameters that were not clinically meaningful. Conclusions: Canagliflozin as monotherapy and as combination therapy was generally well tolerated in patients with T2DM inadequately controlled on their current diabetes mellitus treatment. Keywords: canagliflozin; type 2 diabetes mellitus; sodium glucose cotransporter 2 (SGLT2) inhibitor; antihyperglycemic agent; safety; tolerability

Correspondence: Irina Kline, MD, Janssen Research and Development, LLC, 920 Route 202 South, Raritan, NJ 08869. Tel: 908-927-4154 Fax: 908-927-7977 E-mail: [email protected]

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Introduction

Many patients with type 2 diabetes mellitus (T2DM) do not achieve recommended glycemic goals with currently available antihyperglycemic agents (AHAs)1,2; in addition, some AHAs are associated with adverse events (AEs), including hypoglycemia

© Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.


Safety of Canagliflozin in Patients With T2DM

and weight gain.3 Thus, there is a need for new treatments for T2DM that not only improve glycemic control but also provide positive effects on body weight with a low risk of hypoglycemia, and have a favorable overall safety and tolerability profile. Canagliflozin is an orally active inhibitor of the sodiumglucose cotransporter 2 (SGLT2) developed for the treatment of patients with T2DM.4–12 Sodium-glucose cotransporter 2 is expressed in the proximal tubules of the kidney and is responsible for the majority of renal glucose reabsorption.13,14 Inhibition of SGLT2 by canagliflozin lowers the renal threshold for glucose (RTG; ie, the plasma glucose concentration above which the capacity for renal glucose reabsorption is exceeded), thereby increasing urinary glucose excretion (UGE) and lowering plasma glucose in patients with hyperglycemia.4,15,16 The increased UGE with canagliflozin treatment is associated with a loss of calories leading to body weight reduction, and a mild osmotic diuresis that may contribute to reductions in blood pressure (BP). In addition, canagliflozin lowers the RTG to approximately 80 to 100 mg/dL (4.4 to 5.5 mmol/L),4,15 which is above the threshold for hypoglycemia (typically # 70 mg/dL [3.9 mmol/L]); thus, canagliflozin is expected to be associated with a low risk of hypoglycemia. The insulin-independent mechanism of action of canagliflozin is distinct from the mechanisms of other classes of AHAs, suggesting a potential benefit with canagliflozin treatment in combination with other AHAs. In phase 3 studies, canagliflozin provided improvements in glycemic control and reductions in body weight and BP in patients with T2DM on a variety of background diabetes treatments (ie, diet/exercise alone or with other AHAs).5–12 Across the phase 3 study program, which included a variety of patient populations with T2DM, canagliflozin treatment was generally well tolerated, with increased incidences of specific AEs that may be related to the mechanism of action of SGLT2 inhibitors.17 This report describes findings related to the overall safety and tolerability of canagliflozin based on an integrated analysis of pooled data from placebo-controlled phase 3 studies in a broad range of patients with T2DM inadequately controlled on their current diabetes treatment (diet/exercise ± AHA regimen).

Materials and Methods Study Design, Patient Populations, and Treatments

Safety analyses were performed using a prespecified pooled data set from patients enrolled in 4 placebo-controlled, randomized, phase 3 studies with similar enrollment criteria,

each with a 26-week, double-blind, core treatment period. The studies included in this data set evaluated canagliflozin compared with placebo as monotherapy in patients with T2DM inadequately controlled with diet and exercise only,5 and as combination therapy in patients on background metformin,10 metformin plus sulfonylurea,11 and metformin plus pioglitazone12 (Table 1). Data through Week 26 for randomized patients from each study who received $ 1 dose of canagliflozin 100 or 300 mg or placebo were included in the safety analyses (ie, safety analysis set). The high glycemic substudy (baseline glycated hemoglobin [HbA1c] . 10.0% [86 mmol/mol] and # 12.0% [108 mmol/mol]) of the monotherapy study was not placebo controlled; data from these patients were therefore excluded from this analysis and have been previously published.5 The pooled data set included a broad range of patients with T2DM who were not specifically selected based on particular patient characteristics (other than background diabetes treatment regimen), thus representing a broad and general T2DM experience. Eligible patients included men and women with T2DM who had inadequate glycemic control at screening and at the start of the placebo run-in period while on protocol-specified background diabetes therapy. Key inclusion criteria for each study included in the pooled data set are summarized in Table 1; in general, eligible patients were aged 18 to 80 years, with HbA1c from 7.0% (53 mmol/ mol) to 10.5% (91 mmol/mol) and estimated glomerular filtration rate (eGFR) $ 55 mL/min/1.73 m2 at screening. Key exclusion criteria that were common across the studies included repeated fasting plasma glucose $ 270 mg/dL (15.0 mmol/L) during the pretreatment phase; type 1 diabetes; myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within 3 months prior to screening; and alanine aminotransferase level . 2.0 times the upper limit of normal (ULN) or total bilirubin . 1.5 times the ULN at screening. Across studies, eligible patients were randomly assigned to receive study drug using an Interactive Voice Response System/Interactive Web Response System, with randomization stratified in all studies to ensure adequate distribution across treatment groups of specific patient characteristics (eg, whether a patient required an AHA adjustment period prior to randomization). After randomization, patients were to remain on the stable diabetes treatment (ie, diet/exercise ± AHA regimen) established at the start of the run-in period throughout the double-blind treatment period. Patients who met prespecified glycemic criteria were provided with glycemic rescue therapy; the specific rescue therapy for

© Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 17 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Usiskin et al

Table 1. Study Design and Patient Population Inclusion Criteria Study

Durationa

Age, y

HbA1c, %

Monotherapy Add-on to MET

26 weeks 26 weeks 26 weeks 26 weeks

18-80 18-80 18-80 18-80

7.0-10.0 7.0-10.5 7.0-10.5 7.0-10.5

Add-on to MET + SU Add-on to MET + PIO Overall total, n

Patients Contributing Data to Pooled Analysis, n eGFR, mL/min/1.73 m2 $ 50 $ 55 $ 55 $ 55

PBO 192 183 156 115 646

CANA 100 mg 195 368 157 113 833

CANA 300 mg 197 367 156 114 834

Total 584 918 469 342 2313


a Assessment time point. Abbreviations: CANA, canagliflozin; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; MET, metformin; PIO, pioglitazone; PBO, placebo; SU, sulfonylurea.

each study was selected to be complementary to the type of background AHA therapy specified in each study protocol. In general, during the double-blind treatment period, glycemic rescue therapy was initiated if fasting plasma glucose . 270 mg/dL (15.0 mmol/L) after Day 1 to Week 6, . 240 mg/dL (13.3 mmol/L) after Week 6 to Week 12, and . 200 mg/dL (11.1 mmol/L) after Week 12 to Week 26, and if HbA1c . 8.0% after Week 26. For each study, patients, study center, and sponsor personnel remained blinded to treatment assignment until study completion. All studies included in this analysis were conducted in accordance with ethical principles that comply with the Declaration of Helsinki and are consistent with good clinical practices and applicable regulatory requirements. Study protocols and amendments were approved by institutional review boards/ethics committees at the participating institutions. All patients provided written informed consent prior to participation.

Safety Analyses and Statistical Methods

Regulatory Activities version 14.1. The incidence of AEs was based on the number of patients experiencing $ 1 AE and was summarized by system organ class (SOC), preferred term, and treatment group. The investigator-assessed intensity of AEs was grouped into 2 categories for summary purposes: mild or moderate versus severe. For AEs reported in $ 4 patients in any treatment group, 95% confidence intervals (CIs) for the difference between each canagliflozin dose and placebo were calculated. The AEs with 95% CIs excluding “0” included those for which comparisons with placebo for either the canagliflozin 100 or 300 mg group or for the combined canagliflozin group met this criterion. The binomial exact approach was used for calculation of CIs, and no adjustment was made to control for multiple canagliflozin doses compared with placebo or for multiple preferred terms. The intent of providing the 95% CIs was to identify AEs that required additional clinical assessment; 95% CIs were used as a descriptive review tool and not for formal statistical testing.

Overall AEs

Selected AEs of Interest

Overall safety and tolerability were evaluated based on AE reports, safety laboratory tests (including chemistry, hematology, and urinalysis), 12-lead electrocardiograms, vital sign measurements (BP and pulse rate), self-monitored blood glucose, and physical examinations. A treatment-emergent AE was defined as an AE with an onset after the initiation of double-blind study medication, or within 30 days from the last study medication intake. Adverse events with a start date prior to initiation of double-blind study medication, that were reported to have an increase in severity after initiation of double-blind medication, or that had a change such that the investigator considered that the AE, post-randomization, did have a relationship to study medication (ie, possibly, probably, very likely) were also considered treatment-emergent AEs. The AEs were coded using the Medical Dictionary for

Analyses of selected AEs of interest, including genital mycotic infections, urinary tract infections (UTIs), and AEs related to osmotic diuresis and volume depletion, were performed using prespecified lists of preferred terms constructed using the Medical Dictionary for Regulatory Activities version 14.1. Lists of preferred terms for the analyses of female or male genital mycotic infections, all UTIs or upper UTIs, and AEs related to osmotic diuresis and volume depletion are reported in Tables 2, 3, and 4, respectively. Specific AEs, including genital mycotic infections and UTIs, were also prespecified for collection of additional information using supplemental electronic case report forms. For genital mycotic infections, additional information obtained included those related to treatment. For UTIs, additional information obtained included whether the AE was symptomatic and,

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Table 2. Preferred Terms Used in the Analysis of Female and Male Genital Mycotic Infections

Table 3. Preferred Terms Used in the Analysis of All UTIs and Upper UTIs

Female

Male

All UTIs

Upper UTIs

Genital candidiasis Genital infection, fungal Urogenital infection, fungal Vaginal infection Vaginal inflammation Vulvitis Vulvovaginal candidiasis Vulvovaginal mycotic infection Vulvovaginitis

Balanitis Balanitis candida Balanoposthitis Balanoposthitis infective Erosive balanitis Gangrenous balanitis Genital candidiasis Genital infection Genital infection, fungal Genital infection, male Penile candida Penile infection Posthitis

Bacterial pyelonephritis Bladder candidiasis Cystitis Cystitis bacterial Cystitis escherichia Cystitis gonococcal Cystitis hemorrhagic Cystitis interstitial Cystitis klebsiella Cystitis pseudomonal Emphysematous cystitis Emphysematous pyelonephritis Escherichia UTI Fungal cystitis Genitourinary tract infection Kidney infection Perinephric abscess Pyelocystitis Pyelonephritis Pyelonephritis, acute Pyelonephritis, chronic Pyelonephritis, fungal Pyelonephrosis Pyonephrosis Renal abscess Renal cyst infection Streptococcal UTI Ureter abscess Urethral abscess Urethral carbuncle Urinary bladder abscess Urinary tract abscess UTI UTI, bacterial UTI, enterococcal UTI, fungal UTI, pseudomonal UTI, staphylococcal Urosepsis

Bacterial pyelonephritis Emphysematous pyelonephritis Kidney infection Pyelonephritis, fungal Pyonephrosis Renal abscess Perinephric abscess Pyelonephritis Pyelonephritis, acute Pyelonephritis, chronic Pyelocystitis Pyelonephrosis Renal cyst infection Urosepsis

if symptomatic, the associated signs and/or symptoms (ie, lower tract symptoms of dysuria, frequency, urgency, and/ or suprapubic pain; and upper tract signs and symptoms of flank pain and/or costovertebral pain angle tenderness; fever; chills or rigor; nausea or vomiting).

Hypoglycemia A dedicated supplemental electronic case report form was used to collect information on documented hypoglycemia episodes, which included biochemically confirmed episodes (fingerstick or plasma glucose # 70 mg/dL [3.9 mmol/L]) with or without symptoms and severe episodes (ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness). Because some rescue therapies (eg, sulfonylureas) can lead to hypoglycemia, the primary analysis for documented hypoglycemia was based on data collected prior to the initiation of rescue medication. Given the potential association of some background AHAs (eg, sulfonylurea) with hypoglycemia, results are presented separately based on whether or not patients were on a background therapy associated with hypoglycemia.

Renal Function Assessments Renal function was evaluated through assessment of changes from baseline in parameters including eGFR and blood nitrogen urea (BUN). The proportion of patients meeting predefined criteria for change in eGFR (, 80 mL/min/1.73 m2 and . 30% reduction from baseline, and . 50% reduction from baseline) at any post-baseline assessment and for the last available on-therapy assessment (defined as a measurement obtained # 2 days after the last dose of study drug) were also assessed. Selected renal-related AEs were assessed using a prespecified list of preferred terms (Table 5) including

Abbreviation: UTI, urinary tract infection.

those reflecting a decrease in renal filtration (ie, glomerular filtration rate decreased, blood creatinine increased) and those reflecting acute renal failure AEs (eg, renal failure acute, renal impairment).

Lipid Parameters Blood samples for the assessment of fasting plasma lipids were obtained from patients who had fasted $ 8 hours before blood sample collection. Assessments included triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), non–HDL-C, LDL-C/


Usiskin et al

Table 4. Preferred Terms Used in Analyses of AEs Related to Osmotic Diuresis and Volume Depletion Osmotic Diuresis

Volume Depletion

Dry mouth Dry throat Micturition disorder Micturition urgency Nocturia Pollakiuria Polyuria Polydipsia Thirst Tongue dry Urine output increased

BP, decreased Dehydration Diastolic hypotension Dizziness postural Hypotension Hypovolemia Hypovolemic shock Orthostatic BP, decreased Orthostatic hypotension Orthostatic intolerance Postural orthostatic tachycardia syndrome Presyncope Shock Syncope Urine output decreased


Abbreviations: AE, adverse event; BP, blood pressure.

HDL-C ratio, and total cholesterol. Analysis of lipid parameters included data collected up to a maximum of 2 days after the last dose of study medication. In the event of missing data, the last observation carried forward approach was used to impute missing values. Changes in LDL-C were also evaluated in subgroup analyses based on age (, 65 and $ 65 years), sex (male and female), race (white, black or African American, Asian, and other), body mass index (BMI; , 25, $ 25 to , 30, $ 30 to , 35, and $ 35 kg/m2), eGFR (, 60, $ 60 to , 90, and $ 90 mL/min/1.73 m2), baseline statin use (yes and no), and baseline LDL-C by tertile (ie, # 89, . 89

Table 5. Preferred Terms Used in the Analysis of Selected Renal-related AEs Renal-related AEs Acute phosphate nephropathy Acute prerenal failure Anuria Azotemia Blood creatinine increased Continuous hemodiafiltration Dialysis Glomerular filtration rate decreased Hemodialysis Neonatal anuria Nephropathy toxic Oliguria Peritoneal dialysis Renal failure Renal failure, acute Renal failure, neonatal Renal impairment Renal impairment, neonatal Abbreviation: AE, adverse event.

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to # 120, and . 120 mg/dL [# 2.3, . 2.3 to # 3.1, and . 3.1 mmol/L]). The proportion of patients who shifted from an LDL-C category of , 100 mg/dL (2.59 mmol/L) at baseline to $ 100 mg/dL at Week 26 was assessed.

Other Clinical Laboratory Evaluations For other clinical laboratory parameters (ie, serum chemistry and hematology parameters), percent changes from baseline were evaluated. For selected parameters, the proportion of patients meeting predefined criteria for change at any postbaseline assessment and for the last available on-therapy assessment is also reported. Analysis of clinical laboratory parameters included data collected up to a maximum of 2 days after the last dose of study medication.

Results Patient Disposition and Baseline Characteristics

Across the pooled placebo-controlled studies, a total of 2318 patients were randomized; 2313 patients received $ 1 dose of study drug and were included in the safety analysis set, and 5 patients did not receive the study drug (Table 6). Among randomized patients, 334 (14.4%) discontinued before the Week 26 visit; numerically higher rates of discontinuation were seen with placebo (18.4%) compared with canagliflozin 100 and 300 mg (13.0% and 12.7%, respectively). Reasons for study discontinuation were generally similar across treatment groups. Less than 2% of patients in each of the canagliflozin groups received glycemic rescue therapy before the Week 26 visit, compared with 16.2% of patients in the placebo group. The mean duration of exposure to study drug was approximately 24 weeks for each treatment group (Table 7). The proportion of patients having $ 24 weeks of treatment exposure with canagliflozin 100 and 300 mg and placebo was 87.4%, 87.9%, and 83.1%, respectively. Demographic and baseline characteristics of patients in the pooled data set were generally similar across treatment groups (Table 7). Patients had a mean age of 56 years, with 79% of patients aged 35 to 64 years, 17% aged 65 to 74 years, and 2% aged $ 75 years. The proportions of men and women were approximately equal, with 46% of patients enrolled in study centers in North America, 23% in Europe, 10% in Central/South America, and 22% in the rest of the world. Consistent with the regions of enrollment, 72% of patients were white, 12% were Asian, and 5% were black or African American. Mean BMI was 32.1 kg/m2; . 50% of patients were obese (BMI $ 30 kg/m2). Mean duration of T2DM was 7.3 years. Overall, patients had mild to moderate hypergly-



Table 6. Patient Disposition and Reasons for Discontinuation


Patients, n (%)

Randomized Safety analysis seta Glycemic rescue therapy before Week 26 visitb Discontinued before Week 26 visitb AE Met creatinine or eGFR withdrawal criteriac Death Lack of efficacy on rescue therapy Lost to follow-up Noncompliance with study drug Physician decision Pregnancy Protocol violation Withdrawal of consent Product quality complaint Unable to take protocoldefined rescue therapy Otherd

PBO

CANA 100 mg

CANA 300 mg

Total

648 646

836 833

834 834

2318 2313

8 (1.0)

127 (5.5)

105 (16.2) 14 (1.7)

334 119 (18.4) 109 (13.0) 106 (12.7) (14.4) 21 (3.2) 32 (3.8) 21 (2.5) 74 (3.2) 1 (0.2)

6 (0.7)

4 (0.5)

11 (0.5)

1 (0.2)

0

1 (0.1)

2 (0.1)

5 (0.8)

1 (0.1)

0

6 (0.3)

11 (1.7)

4 (0.5)

17 (2.0)

32 (1.4)

5 (0.8)

9 (1.1)

2 (0.2)

16 (0.7)

3 (0.5) 1 (0.2) 4 (0.6) 30 (4.6) 0

1 (0.1) 1 (0.1) 6 (0.7) 17 (2.0) 1 (0.1)

3 (0.4) 0 3 (0.4) 31 (3.7) 1 (0.1)

7 (0.3) 2 (0.1) 13 (0.6) 78 (3.4) 2 (0.1)

6 (0.9)

1 (0.1)

0

7 (0.3)

31 (4.8)

30 (3.6)

23 (2.8)

84 (3.6)

All randomized patients who received $ 1 dose of study medication. b Percentages based on total randomized patients. c eGFR , 50 mL/min or based on local label contraindications for metformin use. d Includes site terminated by sponsor and categories labeled as “Other, including other study-specific discontinuation criteria” in the monotherapy study, and “Other, including other study-specific withdrawal criteria” in the combination therapy studies. Abbreviations: AE, adverse event; CANA, canagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo. a

cemia at baseline (mean HbA1c 8.0%); 16.6% of patients had poorly controlled hyperglycemia (HbA1c $ 9.0%). Mean baseline eGFR was 88.1 mL/min/1.73 m2. Approximately 19% of patients had microvascular complications and 16% had a history of cardiac disorders.

Overall AEs

The overall incidence of AEs was similar among patients treated with canagliflozin 100 and 300 mg and placebo (60.1%, 59.2%, and 59.4%, respectively; Table 8). The proportion of patients with serious AEs was low and similar across treatment groups (, 4% in each group). The incidence of AEs leading to discontinuation was low overall, but slightly higher with canagliflozin 100 and 300 mg compared with placebo, with no apparent dose relationship (4.3%, 3.6%, and 3.1%, respectively). Across the studies, 4 patients died (2 with placebo, 1 with each canagliflozin dose); none of the deaths were considered by the investigator to be related

to study drug. Overall, most AEs were reported to be mild or moderate in intensity across treatment groups. The most frequently reported AEs across treatment groups (ie, . 10% of patients in any treatment group) were in the infections and infestations, gastrointestinal disorders, and musculoskeletal and connective tissue disorders SOCs; there was no imbalance in the incidences of these AEs across groups (Table 9). Overall, the incidence of AEs by SOC was generally similar across treatment groups. A higher incidence of AEs with canagliflozin compared with placebo was seen in the renal and urinary disorders SOC due to AEs related to osmotic diuresis (eg, thirst, polyuria/pollakiuria [increased urine volume/increased urine frequency]), and in the reproductive system and breast disorders SOC due to genital mycotic infections in males (eg, balanitis [inflammation of the glans penis], balanoposthitis [inflammation of the glans penis and foreskin]) and females (eg, vulvovaginal mycotic infection, vulvovaginal candidiasis). Serious AEs reported in $ 0.2% of patients are listed by SOC and preferred term in Table 10, with similar overall incidences observed across groups. Among AEs that were reported in $ 4 patients in any treatment group, 95% CIs for comparisons of canagliflozin to placebo excluded “0” for 16 AEs. Of these AEs, 2 (hyperglycemia and ligament sprain) had incidences that were higher with placebo than with canagliflozin. Of the 14 AEs with a higher incidence relative to placebo in $ 1 of the canagliflozin groups or in the combined canagliflozin group, 5 specific terms were related to female or male genital mycotic infections (ie, vulvovaginal mycotic infection, vulvovaginitis, balanitis, pruritus genital, vulvovaginal pruritus), and 5 specific terms were related to osmotic diuresis (ie, dry mouth, thirst, polydipsia, pollakiuria, polyuria). The other 4 AEs occurring at a higher incidence with canagliflozin relative to placebo were abdominal pain, pneumonia, tonsillitis, and hyperkalemia. Hyperkalemia was reported in 7 patients in the combined canagliflozin group compared with no patients in the placebo group. None of the hyperkalemia AEs were considered to be related to the study drug by the investigator; hyperkalemia with canagliflozin treatment is further discussed below (see Other Clinical Laboratory Evaluations). The AEs of abdominal pain, pneumonia, and tonsillitis were generally not considered by the investigator to be related to the study drug. To present a safety profile of canagliflozin based on AEs that may have a causal relationship with canagliflozin treatment, incidences of AEs related to canagliflozin


Usiskin et al

Table 7. Baseline Demographic and Disease Characteristics


Characteristic Sex, n (%) Male Female Mean (SD) age, y Race, n (%)a White Black or African American Asian Otherb Region, n (%)a North America Central/South America Europe Rest of the world Mean (SD) HbA1c level, % Mean (SD) BMI, kg/m2 Mean (SD) eGFR, mL/min/1.73 m2 Mean (SD) duration of T2DM, y Patients with microvascular complications, n (%) Patients with cardiac disorders, n (%)c Mean treatment exposure, wk

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

Total (n = 2313)

334 (51.7) 312 (48.3) 56.3 (9.8)

408 (49.0) 425 (51.0) 55.9 (10.1)

404 (48.4) 430 (51.6) 55.7 (9.5)

1146 (49.5) 1167 (50.5) 56.0 (9.8)

470 (72.8) 28 (4.3) 82 (12.7) 66 (10.2)

591 (70.9) 43 (5.2) 103 (12.4) 96 (11.5)

610 (73.1) 48 (5.8) 100 (12.0) 76 (9.1)

1671 (72.2) 119 (5.1) 285 (12.3) 238 (10.3)

303 (46.9) 61 (9.4) 160 (24.8) 122 (18.9) 8.0 (0.9) 31.9 (6.4) 87.0 (19.8) 7.5 (6.2) 127 (19.7) 103 (15.9) 23.8 (5.9)

381 (45.7) 90 (10.8) 176 (21.1) 186 (22.3) 8.0 (0.9) 32.3 (6.4) 88.3 (19.0) 7.2 (5.8) 161 (19.3) 131 (15.7) 24.2 (5.7)

369 (44.2) 88 (10.6) 185 (22.2) 192 (23.0) 8.0 (1.0) 32.0 (6.5) 88.8 (18.9) 7.4 (6.2) 150 (18.0) 132 (15.8) 24.3 (5.5)

1053 (45.5) 239 (10.3) 521 (22.5) 500 (21.6) 8.0 (0.9) 32.1 (6.4) 88.1 (19.2) 7.3 (6.0) 438 (18.9) 366 (15.8) 24.3 (5.6)

Percentages may not total 100.0% due to rounding. Includes American Indian or Alaska Native, Native Hawaiian or other Pacific Islander, multiple, other, unknown, and not reported. c Defined based on the MedDRA v13.1 system organ class for cardiac disorders from medical history. Abbreviations: BMI, body mass index; CANA, canagliflozin; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; MedDRA, Medical Dictionary for Regulatory Activities; PBO, placebo; SD, standard deviation; T2DM, type 2 diabetes mellitus. a

b

treatment (including both pooled and individual preferred terms) that occurred in $ 2% of patients are reported in Table 11. Pooled terms included genital mycotic infections in men (eg, balanitis/balanoposthitis, balanitis candida) and women (eg, vulvovaginal candidiasis, vulvovaginal mycotic infection), UTIs (eg, cystitis, kidney infection), increased urination (eg, polyuria, pollakiuria), and thirst (eg, dry mouth, polydipsia). Individual terms reported included vulvovaginal pruritus, constipation, and nausea.

Table 8. Summary of Overall AEs Patients, n (%)

Any AE AEs leading to discontinuation AEs related to study druga Serious AEs Deaths

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

384 (59.4)

501 (60.1)

494 (59.2)

20 (3.1)

36 (4.3)

30 (3.6)

85 (13.2)

171 (20.5)

191 (22.9)

22 (3.4) 2 (0.3)

28 (3.4) 1 (0.1)

22 (2.6) 1 (0.1)

a Possibly, probably, or very likely related to study drug, as assessed by investigators. Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo.

22

Selected AEs of Interest Genital Mycotic Infections

The incidence of genital mycotic infection AEs in the pooled analysis was higher with canagliflozin 100 and 300 mg compared with placebo in women and men, with a slightly higher incidence seen with canagliflozin 300 mg relative to canagliflozin 100 mg in women (Table 12).18 The incidence of female genital mycotic infection AEs leading to discontinuation was low across treatment groups but higher with both canagliflozin doses compared with placebo; there were no serious genital mycotic infection AEs reported in women across groups. Female genital mycotic infection AEs were generally considered mild to moderate in intensity, as assessed by the investigator, and responded to standard antifungal therapies. The majority of women with a genital mycotic infection AE had a single event; 10 patients in each canagliflozin group and 1 patient in the placebo group had . 1 genital mycotic infection AE (2.4%, 2.3%, and 0.3% of the overall female population in the canagliflozin 100 and 300 mg and placebo groups, respectively). Among the 93 canagliflozin-treated women and 10 placebo-treated women who had a genital mycotic infection AE, the proportion who had . 1 event was 21.5% (20/93) and 10.0% (1/10), respectively.



Table 9. Summary of AEs by SOC


Patients, n (%)

Any AE Blood and lymphatic system disorders Cardiac disorders Congenital, familial, and genetic disorders Ear and labyrinth disorders Endocrine disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Hepatobiliary disorders Immune system disorders Infections and infestations Injury, poisoning, and procedural complications Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Neoplasms benign, malignant, and unspecified (including cysts and polyps) Nervous system disorders Pregnancy, puerperium, and perinatal conditions Psychiatric disorders Renal and urinary disorders Reproductive system and breast disorders Respiratory, thoracic, and mediastinal disorders Skin and subcutaneous tissue disorders Social circumstances Surgical and medical procedures Vascular disorders

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

384 (59.4) 8 (1.2) 11 (1.7) 0 18 (2.8) 2 (0.3) 13 (2.0) 93 (14.4) 39 (6.0) 5 (0.8) 5 (0.8) 191 (29.6) 45 (7.0) 27 (4.2) 41 (6.3) 87 (13.5) 4 (0.6) 49 (7.6) 1 (0.2) 17 (2.6) 14 (2.2) 7 (1.1) 43 (6.7) 31 (4.8) 1 (0.2) 1 (0.2) 21 (3.3)

501 (60.1) 9 (1.1) 13 (1.6) 1 (0.1) 12 (1.4) 4 (0.5) 11 (1.3) 124 (14.9) 49 (5.9) 11 (1.3) 7 (0.8) 248 (29.8) 35 (4.2) 29 (3.5) 51 (6.1) 93 (11.2) 8 (1.0) 74 (8.9) 0 22 (2.6) 61 (7.3) 28 (3.4) 42 (5.0) 41 (4.9) 1 (0.1) 0 19 (2.3)

494 (59.2) 7 (0.8) 18 (2.2) 0 18 (2.2) 2 (0.2) 12 (1.4) 129 (15.5) 62 (7.4) 4 (0.5) 4 (0.5) 242 (29.0) 36 (4.3) 46 (5.5) 41 (4.9) 105 (12.6) 8 (1.0) 65 (7.8) 1 (0.1) 15 (1.8) 52 (6.2) 42 (5.0) 42 (5.0) 41 (4.9) 1 (0.1) 1 (0.1) 25 (3.0)

Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo; SOC, system organ class.

The overall incidence of male genital mycotic infection AEs was low across treatment groups, but higher in the canagliflozin groups than the placebo group, with no evidence of dose-dependency (Table 12). Rates of discontinuation related to male genital mycotic infection AEs were low across treatment groups; there were no serious genital mycotic infection AEs reported in men across groups.

Similar to female genital mycotic infections, male genital mycotic infection AEs were generally considered mild to moderate in intensity, as assessed by the investigator, and responded to standard antifungal therapies. The majority of men with a genital mycotic infection AE had a single event; among the overall male population in the canagliflozin 100 and 300 mg and placebo groups, 2 (0.5%), 5 (1.2%), and

Table 10. Serious AEs in $ 0.2% of Patients in Any Treatment Group Patients, n (%)

Cardiac disorders Acute coronary syndrome Coronary artery disease Infections and infestations Pneumonia Skin and subcutaneous tissue Urticaria Vascular disorders Deep vein thrombosis

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

2 (0.3) 0

0 2 (0.2)

0 0

0

3 (0.4)

0

0

2 (0.2)

0

0

0

2 (0.2)

Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo. © Postgraduate Medicine, Volume 126, Issue 3, May 2014, ISSN – 0032-5481, e-ISSN – 1941-9260 23 ResearchSHARE®: www.research-share.com • Permissions: [email protected] • Reprints: [email protected] Warning: No duplication rights exist for this journal. Only JTE Multimedia, LLC holds rights to this publication. Please contact the publisher directly with any queries.

Usiskin et al

Table 11. AEs Associated With Canagliflozin Treatment That Occurred in $ 2% of Canagliflozin-Treated Patients Patients, n (%)

Female genital mycotic infectionsa,b UTIc Increased urinationd Male genital mycotic infectionse,f Vulvovaginal pruritusa Thirstg Constipation Nausea

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

10 (3.2) 26 (4.0) 5 (0.8) 2 (0.6) 0 1 (0.2) 6 (0.9) 10 (1.5)

44 (10.4) 49 (5.9) 44 (5.3) 17 (4.2) 7 (1.6) 23 (2.8) 15 (1.8) 18 (2.2)

49 (11.4) 36 (4.3) 38 (4.6) 15 (3.7) 13 (3.0) 19 (2.3) 19 (2.3) 19 (2.3)

Percentages based on the number of women in each treatment group (PBO, n = 312; CANA 100 mg, n = 425; CANA 300 mg, n = 430). Includes vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, vaginal infection, vulvitis, and genital infection (fungal). c Includes UTI, cystitis, kidney infection, and urosepsis. d Includes polyuria, pollakiuria, urine output increased, micturition urgency, and nocturia. e Percentages based on the number of men in each treatment group (PBO, n = 334; CANA 100 mg, n = 408; CANA 300 mg, n = 404). f Includes balanitis or balanoposthitis, balanitis candida, and genital infection (fungal). g Includes thirst, dry mouth, and polydipsia. Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo; UTI, urinary tract infection. a


b

0 patients, respectively, had . 1 genital mycotic infection AE. Among the 32 canagliflozin-treated men who had a genital mycotic infection AE, the proportion with . 1 event was 21.9% (7/32).

Urinary Tract Infections The difference in incidence of UTIs with canagliflozin relative to placebo was non–dose-dependent, with a similar incidence observed with canagliflozin 300 mg and placebo and a slightly higher incidence seen with canagliflozin 100 mg (Table 12).19 The incidence of UTI AEs leading to discontinuation was low and similar across treatment groups. The majority of patients with UTI AEs were women (88.3%), with a similar imbalance in UTI AEs seen between the combined canagliflozin group and the placebo group in women (8.7% vs 7.7%) and men (1.4% vs 0.6%). The majority of patients with UTI AEs had symptomatic events (68.5%), with lower tract symptoms most commonly reported (eg, dysuria, frequency, urgency, suprapubic pain). The UTI AEs were generally considered to be mild to moderate in intensity, as assessed by the investigator. The proportion of patients with . 1 symptomatic UTI AE was low and similar across treatment groups (5 [0.6%], 2 [0.2%], and 3 [0.5%] with canagliflozin 100 and 300 mg and placebo, respectively). Among patients with a symptomatic UTI AE, 7/59 (11.9%) patients treated with canagliflozin had . 1 event and 3/17 (17.6%) patients treated with placebo had . 1 event. Incidences of serious UTI AEs were low across treatment groups but numerically higher with both canagliflozin doses compared with placebo; these serious events represented UTI AEs that resulted in hospitalization. There was no notable increase in 24

the incidence of upper UTIs with canagliflozin compared with placebo. In an analysis of 4 symptoms possibly indicative of an upper UTI (ie, flank pain and/or costovertebral angle tenderness, fever . 38.5°C, chills or rigors, nausea or vomiting), the number of patients with $ 2 of these symptoms was small across groups (2 [0.2%], 3 [0.4%], and 0 patients with canagliflozin 100 and 300 mg and placebo, respectively).

AEs Related to Osmotic Diuresis and Volume Depletion In the pooled analysis, incidences of osmotic diuresis–related AEs (eg, thirst, polyuria/pollakiuria) were higher with canagliflozin 100 and 300 mg compared with placebo, with no evidence of dose dependency (Table 13). The majority of osmotic diuresis–related AEs with both canagliflozin doses occurred within the first 6 weeks of treatment, with a subsequent attenuation. Three patients (1 with canagliflozin 100 mg and 2 with canagliflozin 300 mg) discontinued due to an osmotic diuresis–related AE; there were no serious osmotic diuresis–related AEs reported across treatment groups. Osmotic diuresis–related AEs were generally considered mild to moderate in intensity, as assessed by the investigator. The incidence of AEs related to volume depletion (eg, hypotension, postural dizziness, orthostatic hypotension) was low across treatment groups (, 2% per group; Table 13). Incidences of AEs related to volume depletion were numerically higher with canagliflozin 300 mg compared with canagliflozin 100 mg and placebo during the first 18 weeks of treatment, after which the differences between the treatment groups narrowed. There were no reports of AEs related to volume depletion in patients treated with



Table 12. Summary of Genital Mycotic Infection and UTI AEs18,19


Patients, n (%)

Female genital mycotic infection AEa Any AE AEs leading to discontinuation AEs related to study drugb Serious AEs Specific termsc Vulvovaginal mycotic infection Vulvovaginal candidiasis Vulvovaginitis Male genital mycotic infection AEd Any AE AEs leading to discontinuation AEs related to study drugb Serious AEs Specific termsc Balanitis Balanoposthitis Genital infection, fungal UTI AE Any AE AEs leading to discontinuation AEs related to study drugb Serious AEs Specific terms UTI Cystitis Kidney infection Urosepsis Upper UTIs

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

10 (3.2) 0 8 (2.6) 0

44 (10.4) 4 (0.9) 33 (7.8) 0

49 (11.4) 2 (0.5) 45 (10.5) 0

4 (1.3) 3 (1.0) 0

25 (5.9) 7 (1.6) 8 (1.9)

23 (5.3) 12 (2.8) 7 (1.6)

2 (0.6) 0 2 (0.6) 0

17 (4.2) 2 (0.5) 12 (2.9) 0

15 (3.7) 2 (0.5) 12 (3.0) 0

0 1 (0.3) 0

9 (2.2) 4 (1.0) 2 (0.5)

7 (1.7) 3 (0.7) 3 (0.7)

26 (4.0) 1 (0.2) 10 (1.5) 0

49 (5.9) 1 (0.1) 25 (3.0) 2 (0.2)

36 (4.3) 0 21 (2.5) 1 (0.1)

26 (4.0) 0 0 0 0

46 (5.5) 2 (0.2) 0 1 (0.1) 1 (0.1)

34 (4.1) 2 (0.2) 1 (0.1) 0 1 (0.1)

PBO, n = 312; CANA 100 mg, n = 425; CANA 300 mg, n = 430. Possibly, probably, or very likely related to study drug, as assessed by investigators. c The 3 most common terms are shown. d PBO, n = 334; CANA 100 mg, n = 408; CANA 300 mg, n = 404. Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo; UTI, urinary tract infection. a

b

canagliflozin that were serious or led to discontinuation; 1 patient in the placebo group had a serious event and another patient had an AE that led to discontinuation. For patients treated with canagliflozin 100 and 300 mg, AEs related to volume depletion were generally considered to be mild or moderate in intensity, as assessed by the investigator. Among patients who reported a volume depletion–related AE, the majority were on antihypertensive therapy with diuretics, angiotensin-converting enzyme inhibitors, and/or angiotensin receptor blockers at baseline (32.1% on diuretics and 67.9% on angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers).

Hypoglycemia

Incidences of documented hypoglycemia episodes (including biochemically documented episodes [fingerstick or

plasma glucose # 70 mg/dL (3.9 mmol/L)] with or without symptoms and severe episodes [ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness]) are presented separately based on whether patients were on background AHA therapy associated with hypoglycemia (ie, sulfonylurea). In patients not on background sulfonylurea (ie, excluding the study in patients on background metformin plus sulfonylurea), the overall incidence of documented hypoglycemia episodes was low but slightly higher with canagliflozin 100 and 300 mg compared with placebo (Table 14). The number of patients who had glucose values , 56 mg/dL (3.1 mmol/L) was 5 (0.7%), 4 (0.6%), and 2 (0.4%) with canagliflozin 100 and 300 mg and placebo, respectively; the number who had glucose values , 36 mg/dL (2.0 mmol/L) was 1 (0.1%), 0, and 2 (0.4%), respectively. The incidence of severe hypoglycemia


Usiskin et al

Table 13. Summary of AEs Related to Osmotic Diuresis and Volume Depletion


Patients, n (%)

Osmotic diuresis–related AEs Any AE AEs leading to discontinuation AEs related to study druga Serious AEs Specific termsb Pollakiuriac Thirst Polyuriad Volume depletion–related AEs Any AE AEs leading to discontinuation AEs related to study druga Serious AEs Specific termsb Hypotension Dizziness postural Orthostatic hypotension

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

5 (0.8) 0 5 (0.8) 0

56 (6.7) 1 (0.1) 41 (4.9) 0

47 (5.6) 2 (0.2) 41 (4.9) 0

4 (0.6) 1 (0.2) 0

35 (4.2) 11 (1.3) 6 (0.7)

26 (3.1) 16 (1.9) 12 (1.4)

7 (1.1) 1 (0.2) 2 (0.3) 1 (0.2)

10 (1.2) 0 4 (0.5) 0

11 (1.3) 0 6 (0.7) 0

4 (0.6) 2 (0.3) 1 (0.2)

6 (0.7) 3 (0.4) 0

2 (0.2) 4 (0.5) 4 (0.5)

Possibly, probably, or very likely related to study drug, as assessed by investigators. The 3 most common terms are shown. c Increased urine frequency. d Increased urine volume. Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo. a

b

was also low in these patients, with 1 in each canagliflozin group reporting a severe event. An overall higher incidence of documented hypoglycemia episodes was seen across treatment groups in patients on a background of sulfonylurea relative to those not on sulfonylurea. In patients on background sulfonylurea, a dose-related increase in the incidence of documented hypoglycemia episodes was seen with canagliflozin 100 and 300 mg compared with placebo; the incidence of severe hypoglycemia was low and similar across groups (Table 14).

Renal Function Assessments

An initial mean decrease from baseline in eGFR was observed across treatment groups, with a greater decrease with canagliflozin 100 and 300 mg than with placebo (Figure 1). Maximal reductions in eGFR with both canagliflozin doses were seen by Week 6, with subsequent increases through Week 26. Mean changes from baseline to Week 26 in eGFR were –2.1, –3.1, and –1.2 mL/min/1.73 m2 with canagliflozin 100 and 300 mg and placebo, respectively. The BUN levels were increased with both canagliflozin doses by Week 6 and then

Table 14. Summary of Documented Hypoglycemia Episodesa,b Patients, n (%) Patients not on background SU Pooled, PBO-controlled studies, nc Any documented hypoglycemia Severe hypoglycemia Patients on background SU Add-on to MET + SU, n Any documented hypoglycemia Severe hypoglycemia

PBO

CANA 100 mg

CANA 300 mg

490 11 (2.2) 0

676 26 (3.8) 1 (0.1)

678 29 (4.3) 1 (0.1)

156 24 (15.4) 1 (0.6)

157 43 (27.4) 1 (0.6)

156 47 (30.1) 0

Including biochemically documented episodes (fingerstick or plasma glucose # 70 mg/dL [3.9 mmol/L]) with or without symptoms and severe episodes (ie, those requiring the assistance of another individual or resulting in seizure or loss of consciousness). b All events are reported prior to initiation of rescue medication. c Excluding add-on to MET + SU study. Abbreviations: CANA, canagliflozin; MET, metformin; PBO, placebo; SU, sulfonylurea. a

26




Figure 1. Mean eGFR values over time.

Abbreviations: CANA, canagliflozin; eGFR, estimated glomerular filtration rate; PBO, placebo; SE, standard error.

generally stable through Week 26. Mean changes from baseline to Week 26 in BUN were 0.71, 0.76, and 0.01 mmol/L with canagliflozin 100 and 300 mg and placebo, respectively. The proportion of patients with changes in eGFR meeting predefined criteria (ie, , 80 mL/min/1.73 m2 and . 30% reduction from baseline, and . 50% reduction from baseline) was determined to assess potentially clinically important changes in renal function. A higher proportion of patients in the canagliflozin 300 mg group met the eGFR criterion of , 80 mL/min/1.73 m2 and . 30% reduction from baseline compared with the canagliflozin 100 mg and placebo groups (4.1%, 2.0%, and 2.1%, respectively) based upon any postbaseline value. Fewer patients across treatment groups met this criterion when assessed based on the last post-baseline value (0.7%, 1.4%, and 0.5% with canagliflozin 100 and 300 mg and placebo, respectively). The proportion of patients meeting the eGFR criterion of . 50% reduction from baseline based on any post-baseline value was low across groups (1 patient each in the canagliflozin 300 mg and placebo groups, and no patients in the canagliflozin 100 mg group); neither of these 2 patients had a last post-baseline value that was decreased by . 50% from baseline. The incidence of selected renal-related AEs (eg, glomerular filtration rate decreased, blood creatinine increased, renal impairment, renal failure acute) was overall low across treatment groups, but numerically higher with canagliflozin

300 mg relative to canagliflozin 100 mg and placebo (1.7%, 0.6%, and 0.6%, respectively; Table 15). The incidence of renal-related AEs leading to discontinuation was also numerically higher with canagliflozin 300 mg relative to canagliflozin 100 mg and placebo; only 1 serious renal-related AE was reported (with canagliflozin 100 mg).

Fasting Plasma Lipids

In the pooled analysis, canagliflozin was associated with decreases in triglycerides and increases in HDL-C relative to placebo (Table 16). Canagliflozin was also associated with dose-related increases from baseline in LDL-C and total cholesterol compared with placebo, with increases in non–HDL-C that were smaller than those seen in LDL-C. Minimal changes in the LDL-C/HDL-C ratio were observed with canagliflozin, consistent with the generally proportionate increases in LDL-C and HDL-C. Changes in LDL-C were also evaluated in subgroup analyses based on age, sex, race, use of statin medication, and baseline BMI, eGFR, and LDL-C by tertile. For the majority of the subgroups analyzed, including those based on age, sex, race, BMI, and eGFR, the effect of canagliflozin treatment on LDL-C was generally consistent with that seen in the overall population. In the pooled data set, approximately 41% of patients were on statin medication at baseline, and 2.5%, 1.6%, and 2.5% of patients in the canagliflozin 100


Usiskin et al

Table 15. Summary of Selected Renal-related AEs Patients, n (%)

Any AE AEs leading to discontinuation AEs related to study druga Serious AEs Specific terms Glomerular filtration rate decreased Blood creatinine increased Renal impairment Renal failure acute

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

4 (0.6) 1 (0.2) 3 (0.5) 0

5 (0.6) 3 (0.4) 2 (0.2) 1 (0.1)

14 (1.7) 7 (0.8) 8 (1.0) 0

3 (0.5) 1 (0.2) 0 0

2 (0.2) 1 (0.1) 1 (0.1) 1 (0.1)

10 (1.2) 4 (0.5) 1 (0.1) 0


a Possibly, probably, or very likely related to study drug, as assessed by investigators. Abbreviations: AE, adverse event; CANA, canagliflozin; PBO, placebo.

and 300 mg and placebo groups, respectively, initiated or modified statin therapy during the double-blind treatment period. In subgroup analysis by baseline statin use, no meaningful difference was observed in changes in LDL-C with canagliflozin treatment in patients on statins compared with those not on statins. In contrast, changes from baseline in LDL-C were impacted by baseline LDL-C tertile. Placebo-subtracted least squares mean absolute increases in LDL-C were numerically greater in the highest baseline LDL-C tertile compared with the lowest and middle tertiles with both canagliflozin 100 and 300 mg (Table 17); however, a numerically larger placebo-subtracted least squares mean percent increase in LDL-C was seen with canagliflozin in the lowest tertile compared with the middle and highest tertiles. The proportion of patients who shifted from an LDL-C category of , 100 mg/dL (2.59 mmol/L) at baseline to $ 100 mg/dL at Week 26 was higher with canagliflozin 300 mg compared with canagliflozin 100 mg and placebo (30.2%, 23.8%, and 22.8%, respectively).

Other Clinical Laboratory Evaluations

In general, minimal differences were observed between canagliflozin and placebo in mean percent changes in other clinical laboratory parameters (Table 18). Canagliflozin 100 and 300 mg were associated with decreases in serum urate, whereas an increase was observed with placebo (–10.1%, –10.6%, and 1.9%, respectively). There was no notable change from baseline in serum potassium in any treatment group. The proportion of patients with changes in serum potassium meeting the predefined criterion of . ULN (5.4 mmol/L) and . 15% increase from baseline based on any post-baseline value was higher with canagliflozin 28

300 mg relative to canagliflozin 100 mg and placebo (7.0%, 4.4%, and 4.8%, respectively). Related to this, the AE of hyperkalemia was reported in 0.4% of patients in the combined canagliflozin group compared with no patients in the placebo group; no events were serious or led to discontinuation. The AE of blood potassium increased was reported in 0.3% of patients in the combined canagliflozin group compared with 0.2% of patients in the placebo group, with no serious events reported. Increases in serum magnesium were observed with both canagliflozin doses, whereas a small decrease was seen with placebo; no patients had increases in serum magnesium . ULN (1.3 mmol/L) and . 25% increase from baseline. Increases in serum phosphate were also seen with canagliflozin that were higher than those seen with placebo; the proportion of patients with increases in serum phosphate . ULN (1.6 mmol/L) and . 25% increase from baseline at any time post-baseline was 0.6%, 1.6%, and 1.3% with canagliflozin 100 and 300 mg and placebo, respectively. Both canagliflozin doses were associated with increases from baseline in hemoglobin compared with a slight decrease seen with placebo (Table 18); consistent with this, the proportion of patients with increases from baseline in hemoglobin $ 20 g/L (based on any post-baseline value) was higher with canagliflozin 100 and 300 mg relative to placebo (6.0%, 5.5%, and 1.0%, respectively). Commensurate increases in hematocrit were also seen with canagliflozin 100 and 300 mg compared with placebo (5.8%, 6.3%, and 0.2%, respectively).

Discussion

In this pooled analysis of data from placebo-controlled phase 3 studies, canagliflozin 100 and 300 mg were generally well tolerated in patients with T2DM inadequately controlled



Table 16. Summary of Changes in Fasting Plasma Lipids From Baseline to Week 26 (LOCF)a Parameter

PBO (n = 646)

CANA 100 mg (n = 833)

CANA 300 mg (n = 834)

Triglycerides, n Mean ± SD baseline, mg/dL (mmol/L)

564 185.8 ± 114.2 (2.1 ± 1.3) -0.4 ± 3.5 (0.00 ± 0.04) 7.6 ± 1.9

753 182.1 ± 124.6 (2.1 ± 1.4) -9.7 ± 3.2 (-0.11 ± 0.04) 2.4 ± 1.7 -5.2 (-10.0, -0.3) 750 45.9 ± 12.0 (1.2 ± 0.3) 3.7 ± 0.3 (0.09 ± 0.01) 9.4 ± 0.6 5.4 (3.6, 7.2) 746 106.6 ± 36.0 (2.8 ± 0.9) 2.2 ± 1.0 (0.06 ± 0.03) 5.7 ± 1.1 4.5 (1.4, 7.6) 747

741 180.3 ± 122.4 (2.0 ± 1.4) -19.5 ± 3.2 (-0.22 ± 0.04) 0.0 ± 1.7 -7.6 (-12.5, -2.8) 735 46.3 ± 11.6 (1.2 ± 0.3) 4.1 ± 0.3 (0.11 ± 0.01) 10.3 ± 0.6 6.3 (4.5, 8.2) 730 104.4 ± 35.0 (2.7 ± 0.9) 6.0 ± 1.0 (0.15 ± 0.03) 9.3 ± 1.1 8.0 (4.9, 11.1) 729

142.9 ± 43.5 (3.7 ± 1.1) -0.03 ± 1.10 (0.00 ± 0.03) 2.2 ± 0.8 1.5 (-0.9, 3.9) 746 2.5 ± 1.0 -0.13 ± 0.02 -1.4 ± 1.1 -0.6 (-3.7, 2.5) 753 189.0 ± 43.2 (4.9 ± 1.1) 3.7 ± 1.1 (0.10 ± 0.03) 3.4 ± 0.6 2.5 (0.7, 4.3)

139.5 ± 40.7 (3.6 ± 1.1) 2.9 ± 1.1 (0.07 ± 0.03) 4.3 ± 0.8 3.6 (1.2, 6.0) 730 2.4 ± 0.9 -0.07 ± 0.02 0.8 ± 1.1 1.6 (-1.5, 4.8) 741 186.1 ± 41.3 (4.8 ± 1.1) 7.1 ± 1.1 (0.18 ± 0.03) 5.2 ± 0.6 4.3 (2.5, 6.1)

LS mean ± SE change LS mean ± SE percent change Difference vs PBO (95% CI) HDL-C, n Mean ± SD baseline, mg/dL (mmol/L) LS mean ± SE change


LS mean ± SE percent change Difference vs PBO (95% CI) LDL-C, n Mean ± SD baseline, mg/dL (mmol/L) LS mean ± SE change LS mean ± SE percent change Difference vs PBO (95% CI) Non-HDL-C, n Mean ± SD baseline, mg/dL (mmol/L) LS mean ± SE change LS mean ± SE percent change Difference vs PBO (95% CI) LDL-C/HDL-C, n Mean ± SD baseline, mol/mol LS mean ± SE change LS mean ± SE percent change Difference vs PBO (95% CI) Total cholesterol, n Mean ± SD baseline, mg/dL (mmol/L) LS mean ± SE change LS mean ± SE percent change Difference vs PBO (95% CI)

564 45.4 ± 11.0 (1.2 ± 0.3) 1.3 ± 0.3 (0.03 ± 0.01) 4.0 ± 0.7 562 109.5 ± 39.1 (2.8 ± 1.0) -2.2 ± 1.1 (-0.06 ± 0.03) 1.3 ± 1.2 563 146.5 ± 44.8 (3.8 ± 1.2) -2.2 ± 1.2 (-0.06 ± 0.03) 0.7 ± 0.9 562 2.5 ± 1.1 -0.12 ± 0.03 -0.8 ± 1.2 564 191.8 ± 44.3 (5.0 ± 1.1) -0.9 ± 1.3 (-0.02 ± 0.03) 0.9 ± 0.7

Including only patients who had both baseline and post-baseline measurements. Abbreviations: CANA, canagliflozin; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LS, least squares; PBO, placebo; SD, standard deviation; SE, standard error.

a

on their current diabetes treatment (ie, diet/exercise ± AHA regimen). Both canagliflozin doses were associated with an incidence of overall AEs that was similar to that for placebo; incidences of serious AEs were low and similar across groups. The incidence of AEs leading to discontinuation was low across treatment groups, but slightly higher with canagliflozin compared with placebo, largely due to a higher incidence of discontinuations associated with genital mycotic infections and renal-related AEs. Genital mycotic infections, UTIs, and

AEs related to osmotic diuresis were the most commonly reported AEs considered by the investigator to be associated with canagliflozin treatment. In general, these AEs were mild or moderate in intensity, were not serious, and led to few study discontinuations. An increase in the incidence of these AEs has also been seen with other SGLT2 inhibitors,20–24 consistent with these events being related to the mechanism of action of the SGLT2 inhibitor class. Although canagliflozin was not associated with a notable increase in the incidence


30 10.7 (3.5, 17.8)

6.8 (-0.4, 14.1)

0.5 ± 1.7

0.2 ± 1.8 (0.01 ± 0.05)

3.6 (-0.8, 8.0)

4.1 ± 1.5

3.8 (-0.8, 8.3) (0.09 [-0.03, 0.21])

4.0 ± 1.5 (0.10 ± 0.04)

251 105.0 ± 9.2 (2.7 ± 0.2)

CANA 100 mg

6.2 (1.7, 10.6)

6.7 ± 1.5

6.5 (1.9, 11.1) (0.16 [0.04, 0.28])

6.7 ± 1.6 (0.17 ± 0.04)

237 104.3 ± 9.0 (2.7 ± 0.2)

CANA 300 mg

-8.7 ± 1.4

-13.5 ± 2.1 (-0.35 ± 0.06)

203 151.1 ± 26.9 (3.9 ± 0.7)

PBO

b

a

-2.2 ± 2.1 (-0.06 ± 0.06)

231 145.3 ± 20.2 (3.8 ± 0.5)

CANA 300 mg

4.1 (0.3, 7.8)

8.3 (4.5, 12.1)

11.3 5.5 (-0.1, 11.1) (0.15 [0.001, 0.289]) (5.6, 17.0) (0.29 [0.15, 0.44]) -4.7 ± 1.4 -0.4 ± 1.4

-8.0 ± 2.1 (-0.20 ± 0.05)

245 147.1 ± 23.0 (3.8 ± 0.6)

CANA 100 mg

3rd Tertile (. 120 mg/dL [. 3.1 mmol/L])d

Including only patients who had both baseline and post-baseline measurements. For data in mmol/L: PBO, n = 177; CANA 100 mg, n = 250; CANA 300 mg, n = 261. c For data in mmol/L: PBO, n = 180; CANA 100 mg, n = 250; CANA 300 mg, n = 234. d For data in mmol/L: PBO, n = 205; CANA 100 mg, n = 246; CANA 300 mg, n = 235. Abbreviations: CANA, canagliflozin; LDL-C, low-density lipoprotein cholesterol; LOCF, last observation carried forward; LS, least squares; PBO, placebo; SD, standard deviation; SE, standard error.

22.2 ± 2.3

6.8 (2.3, 11.2) (0.18 [0.07, 0.30])

3.6 (-0.8, 8.1) (0.10 [-0.02, 0.22])

18.4 ± 2.4

14.1 ± 1.5 (0.37 ± 0.04)

11.0 ± 1.5 (0.28 ± 0.04)

7.4 ± 1.7 (0.19 ± 0.05)

179 104.0 ± 9.4 (2.7 ± 0.2)

PBO

262 68.3 ± 14.2 (1.8 ± 0.4)

CANA 300 mg

250 68.5 ± 14.2 (1.8 ± 0.4)

180 68.2 ± 13.5 (1.8 ± 0.3)

CANA 100 mg

PBO

LS mean ± SE 11.5 ± 2.8 percent change Difference vs PBO (95% CI)

Patients, n Mean ± SD baseline, mg/dL (mmol/L) LS mean ± SE change, mg/dL (mmol/L) Difference vs PBO (95% CI)

2nd Tertile (. 87 to # 120 mg/dL [. 2.3 to # 3.1 mmol/L])c

1st Tertile (# 87 mg/dL [# 2.3 mmol/L])b

Table 17. Summary of Changes in LDL-C From Baseline to Week 26 by Baseline LDL-C Tertile (LOCF)a


Usiskin et al




Table 18. Summary of Percent Changes in Clinical Laboratory Parameters From Baseline to Week 26 ALT, n Mean baseline, U/L Mean (SD) percent change Alkaline phosphatase, n Mean baseline, U/L Mean (SD) percent change AST, n Mean baseline, U/L Mean (SD) percent change Bilirubin, n Mean baseline, μmol/L Mean (SD) percent change Creatinine, n Mean baseline, μmol/L Mean (SD) percent change GGT, n Mean baseline, U/L Mean (SD) percent change Magnesium, n Mean baseline, mmol/L Mean (SD) percent change Phosphate, n Mean baseline, mmol/L Mean (SD) percent change Potassium, n Mean baseline, mmol/L Mean (SD) percent change Urate, n Mean baseline, μmol/L Mean (SD) percent change Hemoglobin, n Mean baseline, g/L Mean (SD) percent change Hematocrit, n Mean baseline, % Mean (SD) percent change

PBO

CANA 100 mg

CANA 300 mg

522 28.1 2.7 (41.2) 526 77.9 0.0 (15.0) 517 23.3 4.9 (41.4) 523 9.1 2.2 (34.7) 526 74.8 1.5 (10.8) 526 40.7 4.3 (59.8) 526 0.8 -0.6 (7.9) 526 1.2 1.5 (14.7) 523 4.3 0.6 (8.7) 526 332.4 1.9 (17.0) 509 142.3 -1.1 (5.8) 507 42.5 0.2 (6.6)

711 27.8 -7.5 (33.9) 715 76.7 -0.8 (15.3) 703 22.9 -2.9 (26.8) 713 8.6 8.0 (38.5) 715 72.4 2.8 (11.8) 715 36.8 -7.4 (35.2) 714 0.8 8.1 (10.0) 715 1.2 3.6 (14.1) 712 4.3 0.5 (9.7) 715 317.7

714 28.5 -11.1 (34.5) 718 77.0 -3.1 (15.6) 710 23.4 -3.6 (30.2) 717 8.7 9.5 (40.9) 720 72.6 4.0 (11.6) 718 39.7 -11.5 (39.4) 720 0.8 9.3 (9.5) 718 1.2 5.1 (14.7) 716 4.3 1.0 (9.3) 720 321.6

-10.1 (18.3) 706 140.5 3.5 (6.2) 703 41.9 5.8 (7.0)

-10.6 (17.4) 716 140.8 3.8 (6.0) 711 42.0 6.3 (7.1)

Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; CANA, canagliflozin; GGT, gamma glutamyl transferase; PBO, placebo; SD, standard deviation.

of AEs related to volume depletion in this analysis, patients with impaired renal function (eGFR , 60 mL/min/1.73 m2), elderly patients (aged $ 75 years), patients on diuretics or medications that interfere with the renin-angiotensinaldosterone system, and patients with low systolic BP may be at an increased risk of AEs related to volume depletion.17 Due to hemodynamic changes related to osmotic diuresis and reduction in BP, treatment with canagliflozin was associated with a reduction in eGFR that occurred early after initiation of the study drug and subsequently trended back toward baseline; these findings are consistent with those from individual phase 3 studies of canagliflozin, including a study in patients with moderate renal impairment (eGFR $ 30 and , 50 mL/min/1.73 m2).7–9 Similar decreases in eGFR

have also been reported in patients with T2DM with another SGLT2 inhibitor as well as the diuretic hydrochlorothiazide.25 A numerical increase in the incidence of renal-related AEs (predominantly preferred terms of glomerular filtration rate decreased and serum creatinine increased) was also observed with canagliflozin 300 mg, but not canagliflozin 100 mg, relative to placebo. In addition to the evaluation of renal-related AEs, which was based on selection of preferred terms, an assessment based on predefined, objective criteria/cutoffs for change in eGFR was also performed. The observation that the number of patients meeting these eGFR criteria with canagliflozin was smaller when assessed based on the last post-baseline value compared with any post-baseline value is consistent with transient changes in renal function with



Usiskin et al

canagliflozin treatment, and suggests these changes are not likely to be associated with renal injury. Canagliflozin treatment has been shown to reduce RTG to approximately 80 to 100 mg/dL (4.4 to 5.5 mmol/L) in patients with T2DM.4,15 Because this is above the threshold for hypoglycemia (# 70 mg/dL [3.9 mmol/L]), the risk of hypoglycemia with canagliflozin is expected to be low when not used in combination with AHAs that are associated with hypoglycemia (eg, sulfonylureas), consistent with previous reports.5,7–10,12 In this pooled analysis, the incidence of documented hypoglycemia among patients not on background AHAs associated with hypoglycemia was low across treatment groups, as expected. Among patients on background sulfonylurea, overall incidences of hypoglycemia were higher across treatment groups and higher with both canagliflozin doses compared with placebo; the incidence of severe hypoglycemia episodes was low across groups. In a previously reported study in patients with T2DM on background metformin and sulfonylurea,6 the incidence of documented hypoglycemia with canagliflozin 300 mg was not notably different from that observed with sitagliptin 100 mg, which is also not inherently associated with an increased risk of hypoglycemia.26–28 A similar incidence of hypoglycemia with canagliflozin and sitagliptin was observed despite a larger reduction in HbA1c observed with canagliflozin compared with sitagliptin (–1.03% [–11.3 mmol/mol] vs –0.66% [–7.2 mmol/mol], respectively). Across individual phase 3 studies, canagliflozin treatment has been associated with reductions in BP and increases in HDL-C5–12; however, canagliflozin has been associated with dose-related increases in LDL-C. Across the pooled placebocontrolled studies, relative to placebo, canagliflozin 100 and 300 mg showed dose-related increases from baseline in LDL-C (4.5% and 8.0%, respectively), as well as increases in HDL-C (5.4% and 6.3%, respectively) and decreases in triglycerides (–5.2% and –7.6%, respectively). Smaller placebo-subtracted increases in non–HDL-C (1.5% and 3.6%) than in LDL-C and minimal changes in the LDL-C/HDL-C ratio (–0.6% and 1.6%) were observed with canagliflozin 100 and 300 mg, respectively, compared with placebo. In subgroup analyses, no notable differences in changes in LDL-C with canagliflozin were observed based on age, sex, and race, or based on baseline BMI, eGFR, and statin use. In an analysis of LDL-C change based on baseline LDL-C tertile, a numerically greater placebo-subtracted least squares mean absolute increase was seen with canagliflozin in the highest tertile relative to the lowest and middle tertiles; a numerically greater placebo-subtracted least squares mean 32

percent increase was seen in the lowest tertile compared with the middle and highest tertiles. In 2 of the placebo-controlled studies that have been previously reported (monotherapy5 and add-on to metformin10), canagliflozin treatment was associated with smaller increases in apolipoprotein B than in LDL-C. Although the improvements seen in triglycerides and HDL-C are likely related to improvements in glycemic control and reductions in body weight associated with canagliflozin treatment, the mechanism for the increase in LDL-C seen with canagliflozin is not known. These effects may be related to the downstream metabolic effects of UGE, as well as the modest hemoconcentration resulting from the osmotic diuretic effect of canagliflozin.29 Similar changes in lipid parameters have been reported for other SGLT2 inhibitors relative to placebo in patients with T2DM.24,30 Because LDL-C is an established cardiovascular risk factor and an accepted surrogate endpoint, the impact of these changes are currently under evaluation in a larger cardiovascular assessment study.31 Generally, minimal differences in safety laboratory parameters were observed between canagliflozin and placebo across the placebo-controlled studies. A small increase in the proportion of patients meeting a predefined criterion for increased serum potassium was observed with canagliflozin 300 mg compared with placebo, and hyperkalemia AEs were reported in more patients in the combined canagliflozin group compared with the placebo group. Increases in hemoglobin (and commensurate rises in hematocrit) were seen with canagliflozin relative to placebo, likely reflecting hemoconcentration associated with the diuretic effect of canagliflozin. These rises in hemoglobin infrequently led to values above the ULN and were not generally reported as AEs.

Conclusions

Canagliflozin as monotherapy and combined with other AHAs was generally well tolerated across a pooled population of patients with T2DM inadequately controlled with their current AHA therapy. Canagliflozin was associated with increased incidences of AEs related to its mechanism of action of increased UGE (eg, genital mycotic infections) and osmotic diuresis (eg, thirst, polyuria/pollakiuria), without increases in serious AEs. As anticipated, canagliflozin was associated with a low risk of hypoglycemia in patients not on background sulfonylurea. Taken together, these findings support the safety and tolerability of canagliflozin across a range of patients with T2DM alone or in combination with other AHAs.




Acknowledgments

The studies described in this manuscript were sponsored by Janssen Research & Development, LLC. The sponsor had a role in the study design and conduct, and in data collection, analysis, and interpretation. The authors prepared the report with editorial assistance funded by the sponsor. All authors had full access to study data, were responsible for the integrity of the data and the accuracy of the data analysis, and reviewed, edited, and approved the report for publication. The authors thank all the investigators, study teams, and patients for participating in these studies. Editorial support was provided by Katie McClendon, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.

Conflict of Interest Statement

Keith Usiskin, MD, Irina Kline, MD, Albert Fung, BS, Cristiana Mayer, PhD, and Gary Meininger, MD, are current or former full-time employees of Janssen Research and Development, LLC. Albert Fung, BS, holds Johnson and Johnson stock and stock options. Keith Usiskin, MD, is an employee of Celgene Corporation.

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