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.¹
• A phase 1, 2-week, open-label, multiple-dose study assessing the pharmacokinetics (PK) and pharmacodynamics (PD) of canagliflozin in pediatric patients with type 2 diabetes mellitus (T2DM) found that canagliflozin 100 mg and 300 mg had PK and PD characteristics similar to those observed in adult patients with T2DM.²
• A phase 3, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of INVOKANA 100 mg and 300 mg in children and adolescents with T2DM is currently ongoing.³

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).²

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 estimated glomerular filtration rate (eGFR) of ≥90 mL/min/1.73 m² and a glycosylated hemoglobin (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.
• Adverse events 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

• Treatment-emergent AEs (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.

Ongoing Study

An ongoing, phase 3, randomized, multicenter, double-blind, parallel-group, placebo-controlled study will evaluate the efficacy and safety of INVOKANA 100 mg and 300 mg in children and adolescents with T2DM.³ For additional information, please visit: https://clinicaltrials.gov/ct2/show/study/NCT03170518.

• Patients with T2DM included in the study were aged 10 to 17 years, with random C-peptide at screening >0.6 ng/mL (>0.2 nmol/L), and HbA1C of ≥6.5% to ≤11.0% and either:
  • on diet and exercise alone for at least 4 weeks prior to screening
  • on diet and exercise and a stable dose of metformin monotherapy ≥1,000 mg per day for at least 8 weeks prior to screening
  • on diet and exercise and a stable insulin monotherapy regimen for at least 8 weeks prior to screening
  • on diet and exercise and a stable combination therapy with metformin and insulin for at least 8 weeks prior to screening
• After a 2-week, single-blind, placebo run-in period, patients were randomized to INVOKANA 100 mg or placebo once daily during the first 12 weeks. At week 13, patients with HbA1c of ≥7.0% and eGFR ≥60 mL/min/1.73 m² will be re-randomized to either remain on INVOKANA 100 mg or placebo or up titrated to INVOKANA 300 mg or placebo until week 52.
• Primary endpoint (week 26): change in HbA1C from baseline at week 26.
• Secondary endpoints (weeks 26 and 52): change from baseline in fasting plasma glucose and body weight; percent of patients achieving HbA1C <7.5%, <7%, and <6.5%; percent of patients receiving rescue therapy; and time to rescue therapy.
• Other outcomes (weeks 26 and 52): change from baseline in BMI, systolic and diastolic blood pressure, lipids, HbA1C (weeks 12 and 52), growth velocity, Tanner staging, bone marker turnover, and urinary albumin to creatinine ratio.

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.