SUMMARY

• INVOKANA is indicated as an adjunct to diet and exercise to improve glycemic control in adults and pediatric patients aged 10 years and older with type 2 diabetes mellitus (T2DM).¹
• A phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel-group, international study evaluated the efficacy and safety of INVOKANA 100 mg and 300 mg in children and adolescents (aged 10 to 17 years) with T2DM and found that both INVOKANA doses demonstrated a clinically meaningful reduction in glycosylated hemoglobin (HbA1c).²
• A phase 1, 2-week, open-label, multiple-dose study assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric patients with T2DM found that canagliflozin 100 mg and 300 mg had PK and PD characteristics similar to those observed in adult patients with T2DM.³

CLINICAL DATA

Phase 3 clinical study

A phase 3, randomized, multicenter, double-blind, placebo-controlled, parallel-group, international study evaluated the efficacy and safety of INVOKANA 100 mg and 300 mg in children and adolescents with T2DM (N=171).² 

Study Design/Methods

• A total of 171 children and adolescents aged ≥10 to <18 years who were diagnosed with T2DM and had inadequate glycemic control (HbA1c ≥6.5% and ≤11%) were included.
• Eligible patients had either:
  • Followed a diet and performed exercise alone for ≥4 weeks or
  • Received a stable dose of metformin monotherapy (≥1000 mg/day or the maximum tolerable dose), stable dose of insulin monotherapy (≤15% change in the total daily insulin), or combination of metformin and insulin for ≥8 weeks before screening
• All patients were randomized 1:1 to receive either INVOKANA 100 mg (n=84) or placebo (n=87) once daily during the first 12 weeks. The HbA1c level and estimated glomerular filtration rate (eGFR) were evaluated at week 12.
• At week 13, patients with HbA1c ≥7.0% and eGFR ≥60 mL/min/1.73 m² were rerandomized to either continue INVOKANA 100 mg (or placebo) or have their INVOKANA dose uptitrated to 300 mg (or their placebo dose mock uptitrated to match INVOKANA 300 mg) until week 52.
• Primary endpoint: change in HbA1c from baseline at week 26.
• Key secondary endpoints (weeks 26 and 52): change in HbA1C from baseline to week 52; change in fasting plasma glucose and body weight were measured at both week 26 and 52; percentage of patients achieving HbA1C <6.5%, <7%, and <7.5% at weeks 26 and 52; percentage of patients receiving rescue therapy; time to rescue therapy; safety assessment; and physical development.
• Safety assessment: adverse events (AEs), hypoglycemic events, physical examinations, laboratory assessments, and vital signs.

Results

Patient Characteristics

• Treatment exposure was similar between the INVOKANA and placebo groups, with a mean duration of 338 and 335 days, respectively.
• Baseline demographic and clinical characteristics were balanced between the treatment groups. The key demographic and clinical characteristics are presented in Table: Key Baseline Demographic and Clinical Characteristics.

Efficacy

• At week 26, patients treated with INVOKANA experienced a significantly greater r in HbA1c from baseline compared with patients receiving placebo (least square [LS] mean difference, -0.76%; 95% confidence interval [CI], -1.25 to -0.27; P=0.002).
  • Similar results were observed among patients receiving background metformin with or without insulin (LS mean difference, -0.77%; 95% CI, -1.38 to -0.17; P=0.012).
  • Patients treated with INVOKANA experienced a significant reduction in the fasting plasma glucose level compared with patients receiving placebo at week 26 (LS mean difference, -1.42 mmol/L [-25.5 mg/dL]) and week 52 (LS mean difference, -1.54 mmol/L [-27.8 mg/dL]).
• At week 26, a significantly higher proportion of patients treated with INVOKANA achieved the target HbA1c levels compared with those receiving placebo.
  • HbA1c <6.5% was achieved by 36.3% of patients treated with INVOKANA vs 14.0% of patients receiving placebo (difference, 22.3 percentage points; CI, 10.5-34.1).
  • HbA1c <7.0% was achieved by 45.7% of patients treated with INVOKANA vs 32.8% of patients receiving placebo (difference, 12.9 percentage points; CI, 0.8-25.0).
• At week 52, a significantly greater proportion of participants treated with INVOKANA achieved the target HbA1c levels compared with those receiving placebo.
  • HbA1c <6.5% was achieved by 30.9% of patients in the INVOKANA group vs 15.6% of patients in the placebo group (difference, 15.2 percentage points; CI, 3.4-27.1).
  • HbA1c <7.0% was achieved by 47.2% of patients in the INVOKANA group vs 28.9% of patients in the placebo group (difference, 18.3 percentage points; CI, 6.6-30.0).
• Up to week 52, 11.9% of patients (n=10) in the INVOKANA group required rescue medication vs 46.0% of patients (n=40) in the placebo group. The time to initiate rescue medication was longer in patients receiving INVOKANA than in those receiving placebo.

Safety

• Treatment-emergent AEs (TEAEs) were reported more frequently (≥2%) in the INVOKANA group compared to the placebo group; these TEAEs included headache (10.7% vs 3.4%), nasopharyngitis (9.5% vs 5.7%), urinary tract infection (7.1% vs 4.6%), and vomiting (6.0% vs 2.3%).
• Serious AEs were reported in 8 (9.5%) patients in the INVOKANA group and 5 (5.7%) patients in the placebo group.
• Genital mycotic and bacterial infections were reported in the INVOKANA group; these infections included candida balanitis (2 [2.4%]), vulvovaginal candidiasis (2 [2.4%]), bacterial vaginosis (1 [1.2%]), and fungal genital infection (1 [1.2%]).
• No deaths, cancer, or cardiovascular events were reported during the study.
• Symptomatic hypoglycemia was reported in 10 (11.9%) patients in the INVOKANA group and 9 (10.3%) patients in the placebo group.
• Laboratory-documented hypoglycemia (blood glucose ≤3.9 mmol/L or ≤70 mg/dL) was reported in 15 (17.9%) patients in the INVOKANA group and 14 (16.1%) patients in the placebo group.
• Hypoglycemic episodes with blood glucose <3.1 mmol/L (56 mg/dL) was reported in 6 (7.1%) patients in the INVOKANA group and 7 (8.0%) patients in the placebo group.
• Hypoglycemia episodes with blood glucose <2.0 mmol/L (<36 mg/dL) was reported in 2 (2.3%) patients in the placebo group.

Phase 1 clinical studies

PK/PD Study

A phase 1, 2-week, open-label, multiple-dose, multicenter study assessed the PK and PD of canagliflozin in pediatric patients with T2DM (N=17).³

Study Design/Methods

• Patients were enrolled into 2 cohorts sequentially (canagliflozin 100 mg group, n=8; canagliflozin 300 mg group, n=9).
• Patients with T2DM aged 10 to 17 years who were on a stable regimen of metformin immediate-release monotherapy of ≥1000 mg/day for ≥8 weeks prior to screening were eligible for inclusion. Patients also had to have an eGFR of ≥90 mL/min/1.73 m² and HbA1c level between 6.1% and 10.0%.
• Placebo was administered on day -1, followed by 14 days of open-label treatment with either a single daily dose of canagliflozin 100 mg or canagliflozin 300 mg.
• PK and PD were assessed over a 24-hour period on days 14-17.
• AEs were assessed from days 1-14.

Results

Patient Characteristics

• Patient demographics and baseline characteristics were generally similar between groups. Mean age was 14.6 years, mean body weight was 107.2 kg, mean body mass index (BMI) was 38.2 kg/m², mean HbA1c was 6.9%, 71% of patients were black/African American, and 24% of patients were Hispanic/Latino.

PK

• Maximum plasma concentration (C_max) was observed at 1.6 hours and 2.4 hours in the canagliflozin 100 mg group and canagliflozin 300 mg group, respectively. Mean C_max values were 9.5±4.3 ng/mL/mg and 10.9±4.4 ng/mL/mg, respectively, and corresponding mean AUC values were 61.9±17.7 and 94.6±41.4 h·ng/mL/mg, respectively.
• The elimination half-life was 11.3±2.5 hours and 15.2±6.9 hours in the canagliflozin 100 mg group and canagliflozin 300 mg group, respectively.
• Other PK parameters in the pediatric patients receiving either 100 or 300 mg once-daily doses of canagliflozin in this study were generally consistent with those of adult patients with T2DM in prior studies.

PD

• On day 14, a decrease in mean 24-hour renal threshold for glucose (RT_G) to 84.6±13.8 mg/dL and 69.1±9.6 mg/dL was observed with canagliflozin 100 mg and 300 mg, respectively.
  • In the canagliflozin 100 mg group, near-maximal effects were observed over the first 12 hours, with modest attenuation of action from 12-24 hours. With the canagliflozin 300 mg group, near-maximal lowering of the RT_G was observed over the entire 24-hour period, with results consistent with findings in adults.
• Mean 24-hour urinary glucose excretion increased from 5.3±10.5 g at baseline to 74.1±37.4 g with canagliflozin 100 mg, and from 0.1±0.04 g at baseline to 68.6±26.5 g with canagliflozin 300 mg.
• Both canagliflozin 100 mg and 300 mg reduced plasma glucose throughout the 24-hour period, with greater reduction in plasma glucose observed in patients with higher vs lower baseline fasting plasma glucose.

Safety

• TEAEs were reported in 9/17 (52.9%) patients, with no apparent dose relationship (canagliflozin 100 mg group, n=4; canagliflozin 300 mg group, n=9).
  • Nausea was the most commonly reported TEAE (n=3). All other TEAEs (ie, abdominal pain, vomiting, hypoglycemia, metabolic acidosis, onychoclasis, rash, upper respiratory tract infection, and headache) were reported by a single patient.
• All TEAEs were reported as mild in severity, with the exception of metabolic acidosis.
• No deaths, serious TEAEs, or study drug discontinuations due to TEAEs were reported.

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 08 November 2024.