Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Label indication INVOKANA (canagliflozin) is indicated: as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. to reduce the risk of major adverse cardiovascular events (cardiovascular death, nonfatal myocardial infarction and nonfatal stroke) in adults with type 2 diabetes mellitus and established cardiovascular disease (CVD). FDA label
Also known as Canagliflozin (JNJ-28431754), Canagliflozin tablets
Canagliflozin · 58 trials · 15 indications
Change from baseline in KCCQ-TSS was reported. KCCQ was a 23-item, self-administered questionnaire that measure the participant's perception of their health status, including their heart failure (HF) symptoms, impact on physical and social function and how their HF impacts the quality of life. KCCQ quantifies 7 domains: physical limitations (6 items), symptom stability (1 item), symptom frequency (4 items), symptom burden (3 items), self-efficacy (2 items), quality of life (3 items) and social limitations (4 items). Scores were generated for each domain and scaled from 0 to 100, with 0 denoting the worst and 100 the best possible status. KCCQ-TSS was average of domains- symptom frequency and symptom burden, and transformed to a single score which ranged from 0 (worst) to 100 (the best possible status), where the higher score reflected better health status.
Change from baseline in HbA1c at Week 26 was analyzed using a pattern mixture model with multiple imputation. Data for this outcome measure was planned to be collected and analyzed for the combined population of arm Canagliflozin 100 mg and Canagliflozin 300 mg.
An AE was any untoward medical occurrence in a clinical study participant administered a pharmaceutical (investigational or non investigational) product. An AE did not necessarily have a causal relationship with the pharmaceutical/biological agent under study. TEAE was defined as the AEs occurring after first administration of double blind study intervention up to 30 days post last dose of study intervention.
Primary composite endpoint is the composite of DoSC, ESKD, and renal or CV death. DoSC: from baseline average determination (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). ESKD: as initiation of maintenance dialysis for at least 30 days, or renal transplantation, or an estimated glomerular filtration rate (eGFR) value of less than (\<)15 milliliters per minute per 1.73 square meter (mL/min/1.73 m\^2) (sustained and confirmed by repeat central laboratory measure after at least 30 days and preferably within 60 days). Renal death: death in participants who had reached ESKD, died without initiating renal replacement therapy, and no other cause of death was determined via adjudication. Adjudication of these events by Endpoint Adjudication Committee (EAC) was performed in blinded fashion. Event rate estimated based on time to first occurrence of primary composite endpoint are presented.
The change in the value of glycated hemoglobin (the concentration of glucose bound to hemoglobin as a percent of the absolute maximum that can be bound) from baseline at Week 26 was compared between the different treatment groups.
The table below shows the least-squares (LS) mean change in HbA1c from baseline to Week 18 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 52 for each treatment group. The statistical analysis shows the treatment difference (ie, between canagliflozin and sitagliptin) in the LS mean change.
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 26 for each treatment group in patients randomized to the High Glycemic Substudy.
MACE, defined as a composite of CV death, non-fatal MI, and nonfatal stroke. Adjudication of these events by the Endpoint Adjudication Committee (EAC) was performed in a blinded fashion. Event rate estimated based on the time to the first occurrence of MACE are presented.
The percent change from baseline in body weight at Week 26 was analysed.
Clinical response at Weeks 18 was assessed by the percentage of participants with Hemoglobin A1c (HbA1c) reduction greater than or equal to 0.4 % and had no increase in body weight.
The table below shows the least-squares (LS) mean change in HbA1c from Baseline to Week 18 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the LS mean change.
The table below shows the mean percent change in body weight from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin group minus placebo) in the least-squares mean percent change.
The table below shows the mean change in HbA1c from Baseline to Week 12 for each treatment group. The statistical analyses show the treatment differences (ie, each canagliflozin or sitagliptin group minus placebo) in the least-squares mean change.
The Cmax is the maximum observed plasma concentration of metformin.
The AUClast is the area under the plasma concentration-time curve from time 0 to the time of the last observed quantifiable concentration (Clast).
The AUC (0-infinity) is the area under the plasma concentration-time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration-time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
The AUClast is the area under the plasma concentration time curve from time 0 to the time of the last observed quantifiable concentration (Clast).
The AUC (0-infinity) is the area under the plasma concentration time curve from time zero to infinite time, calculated as the sum of AUC(last) and C(last)/lambda(z); wherein AUC(last) is area under the plasma concentration time curve from time zero to last quantifiable time, C(last) is the last observed quantifiable concentration, and lambda(z) is elimination rate constant.
Plasma concentrations of metformin are used to evaluate how much metformin is in the blood over time.
Plasma concentrations of canagliflozin are used to evaluate how much canagliflozin is in the blood, 2 hours after dosing.
Plasma concentrations of canagliflozin are used to evaluate how long canagliflozin stays in the body.
Plasma concentrations of canagliflozin are used to evaluate how long canagliflozin stays in the body.
Plasma concentrations of metformin are used to evaluate how long it stays in the body.
Plasma concentrations of canagliflozin are used to evaluate how long canagliflozin stays in the body.
Plasma concentrations of metformin are used to evaluate how long metformin stays in the body.
Plasma concentrations of metformin are used to evaluate how long it stays in the body.
Renal threshold is defined as the plasma glucose concentration above which glucose is excreted in the urine.
Parameters are volume of distribution (Vd), clearance (CL) and half life (T1/2)
Baseline is defined as up to 3 days predose (Week -1)
Treatment-related adverse events are adverse events with onset during the treatment phase.
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Baseline is defined as up to 3 days predose (Week -1)
Comparison of the maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC) of canagliflozin (JNJ-28431754) (measures of the body's exposure to canagliflozin) before and after administration of a single dose of cyclosporine. This will be used to determine whether there is a pharmacokinetic interaction between cyclosporine and canagliflozin.
Comparison of plasma concentrations of digoxin following administration of digoxin alone (Treatment A) or in combination with canagliflozin (JNJ-28431754) (Treatment B). This will be used to determine whether there is a pharmacokinetic interaction between digoxin and canagliflozin.
Comparison of the urine concentrations of digoxin following administration of digoxin alone (Treatment A) or in combination with canagliflozin (JNJ-28431754) (Treatment B). This will be used to determine whether there is a pharmacokinetic interaction between canagliflozin and digoxin.
Comparison of plasma concentrations of simvastatin following administration of a single dose of simvastatin alone or in combination with multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacokinetic interaction between simvastatin and canagliflozin.
Comparison of plasma concentrations of the active metabolite of simvastatin following administration of a single dose of simvastatin alone or in combination with multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacokinetic interaction between simvastatin and canagliflozin.
Comparison of plasma HMG-CoA reductase inhibitory activity following administration of a single dose of simvastatin alone or in combination with multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacodynamic interaction between simvastatin and canagliflozin. (Simvastatin lowers cholesterol by inhibiting the activity of the enzyme HMG-CoA reductase).
Plasma concentrations of canagliflozin (JNJ-28431754), following the administration of a single 200mg dose and a single 300 mg dose, will be used to determine pharmacokinetic parameters for canagliflozin (measurements describing how the body affects the drug).
Urine concentrations of canagliflozin (JNJ-28431754), following the administration of a single 200mg dose and a single 300 mg dose, will be used to determine pharmacokinetic parameters for canagliflozin (measurements describing how the body affects the drug).
Change from baseline in 24-hour urine glucose excretion following the administration of a single 200 mg dose and a single 300 mg dose of canagliflozin (JNJ-28431754) will be used to evaluate the pharmacodynamics of canagliflozin (ie, how the drug affects the body).
Change from baseline in the area under the plasma glucose concentration-time curve (AUC) (a measure of the body's exposure to glucose) at 4 hours following the administration of a single 200mg dose and a single 300 mg dose of canagliflozin (JNJ-28431754) will be used to assess the pharmacodynamics of canagliflozin (ie, how the drug affects the body).
Change from baseline in the area under the plasma insulin concentration-time curve (AUC) (a measure of the body's exposure to insulin) at 4 hours following the administration of a single 200mg dose and a single 300 mg dose of canagliflozin (JNJ-28431754) will be used to assess the pharmacodynamics of canagliflozin (ie, how the drug affects the body).
Change from baseline in the area under the plasma C-peptide concentration-time curve (AUC) (a measure of the body's exposure to C-peptide) at 4 hours following the administration of a single 200mg dose and a single 300 mg dose of canagliflozin (JNJ-28431754) will be used to assess the pharmacodynamics of canagliflozin (ie, how the drug affects the body).
Comparison of plasma concentrations of glyburide following administration of a single dose of glyburide alone or in combination with multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacokinetic interaction between glyburide and canagliflozin.
Comparison of plasma concentrations of glyburide metabolites following administration of a single dose of glyburide alone or in combination with multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacokinetic interaction between glyburide and canagliflozin.
QT intervals (assessment of the electrical activity of the heart) will be measured from 12-lead electrocardiogram (ECG) readings and will be corrected for heart rate. The corrected QT intervals (QTc) obtained following single doses of 300 mg canagliflozin (JNJ-28431754), 1,200 mg canagliflozin, and 400 mg moxifloxacin, will be compared with QTc intervals obtained following dosing with placebo.
Plasma concentrations of canagliflozin (JNJ-28431754) following the administration of a single dose of canagliflozin will be used to determine pharmacokinetic parameters for canagliflozin (measurements describing how the body affects the drug) in varying degrees of kidney function.
Change from baseline in 24-hour urine glucose excretion following the administration of a single dose of canagliflozin (JNJ-28431754) will be used to evaluate the pharmacodynamics of canagliflozin (ie, how the drug affects the body) in varying degrees of kidney function.
Plasma concentrations of canagliflozin (JNJ-28431754) metabolites following the administration of a single dose of canagliflozin will be used to determine pharmacokinetic parameters for canagliflozin metabolites (measurements describing how the body affects the metabolites) in varying degrees of kidney function.
Comparison of plasma concentrations of ethinyl estradiol and levonorgestrel, before and after administration of multiple doses of canagliflozin (JNJ-28431754). This will be used to determine whether there is a pharmacokinetic interaction between multiple doses of canagliflozin and single doses of an oral contraceptive containing ethinyl estradiol and levonorgestrel.
Cmax (a measure of the body's exposure to canagliflozin \[JNJ-28431754\]) will be compared before and after administration of a single dose of metformin.
AUC (a measure of the body's exposure to canagliflozin \[JNJ-28431754\]) will be compared before and after administration of a single dose of metformin.
Cmax (a measure of the body's exposure to metformin will be compared before and after administration of multiple doses of canagliflozin (JNJ-28431754).
AUC (a measure of the body's exposure to metformin will be compared before and after administration of multiple doses of canagliflozin (JNJ-28431754).
24-hour urine glucose excretion will be compared following a single dose of metformin, multiple doses of canagliflozin (JNJ-28431754), or multiple doses of canagliflozin in combination with a single dose of metformin.
24-hour area under the serum glucose concentration-time curve will be compared following a single dose of metformin, multiple doses of canagliflozin (JNJ-28431754), or multiple doses of canagliflozin in combination with a single dose of metformin.
The change from baseline in urine excretion per day will be compared following escalating doses of canagliflozin (JNJ-28431754).
The change from baseline in urine excretion per hour will be compared following escalating doses of canagliflozin (JNJ-28431754).
Visual analog scale (VAS) scores will be obtained from the VAS questionnaire. In the VAS questionnaire, volunteers mark a point on a line (drawn between 2 statements) to indicate how they feel about the statements. The statements about hunger are as follows: "I am not hungry at all" and "I have never been hungrier". Other statements relate to satiety (feeling satisfied), feeling full and prospective food consumption. Scores will be compared following escalating doses of canagliflozin (JNJ-28431754).
The change from baseline in mean 24-hour plasma glucose concentrations will be compared following escalating doses of canagliflozin (JNJ-28431754).
| Arm | Type | Description |
|---|---|---|
| Canagliflozin 100 mg | EXPERIMENTAL | Participants will be administered 100 milligram (mg) immediate-release, over-encapsulated tablets (as a capsule) orally once daily for 12 weeks. |
| Placebo | PLACEBO_COMPARATOR | Participants will be administered matching placebo capsules orally once daily for 12 weeks. |
| Single-blind run-in Period: Placebo | EXPERIMENTAL | Participants will receive 1 placebo tablet matching canagliflozin 100 milligram (mg) once-daily during the 2-week single-blind placebo run-in period. |
| Double-blind Treatment Phase: Canagliflozin or Placebo | EXPERIMENTAL | Canagliflozin 100 mg/matching placebo once-daily during first 12 weeks. At Week 13, participants who have glycated hemoglobin (HbA1c) of greater than or equal to (\>=)7.0 percent (%), estimated glomerular filtration rate (eGFR) \>=60 milliliter/minute/1.73 meter square (mL/min/1.73 m\^2) will be re-randomized to either remain on canagliflozin 100 mg/matching placebo or up-titrate to canagliflozin 300 mg/matching placebo till Week 52. |
| Canagliflozin 300 mg | EXPERIMENTAL | Participants will receive one 300 mg canagliflozin capsule before the morning meal and one matching placebo capsule with the evening meal plus placebo tablets with the evening meal (to match the metformin XR tablets administered in other treatment arms) for 26 weeks. |
| Metformin XR | EXPERIMENTAL | Participants will receive metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal, plus one placebo capsule before the morning meal and one placebo capsule with the evening meal (to match the canagliflozin capsules administered in other treatment arms) for 26 weeks. |
| Canagliflozin 100 mg + Metformin XR | EXPERIMENTAL | Participants will receive one 100 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks. |
| Canagliflozin 300 mg + Metformin XR | EXPERIMENTAL | Participants will receive one 300 mg canagliflozin capsule with the evening meal and one matching placebo capsule before the morning meal plus metformin XR tablets (in doses titrated over 9 weeks) once daily with the evening meal for 26 weeks. |
| Canagliflozin 100mg | EXPERIMENTAL | Each participant will receive 100 mg of canagliflozin once daily for 18 weeks with protocol-specified doses of metformin alone or metformin plus sulphonylurea. |
| Canagliflozin 300mg | EXPERIMENTAL | Each participant will receive 300 mg of canagliflozin once daily for 18 weeks with protocol-specified doses of metformin alone or metformin plus sulphonylurea. |
| Sitagliptin 100 mg | ACTIVE_COMPARATOR | Each patient will receive 100 mg of sitagliptin once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea |
| Placebo/Sitagliptin | OTHER | Each patient will receive matching placebo once daily for 26 weeks with stable doses of metformin and pioglitazone. At Week 26, patients will be switched from placebo to 100 mg of sitagliptin once daily with stable doses of metformin and pioglitazone until Week 52. |
| Canagliflozin (JNJ-28431754) 100 mg | EXPERIMENTAL | Each patient will receive canagliflozin (JNJ-28431754) 100 mg once daily on background standard of care for diabetes once daily for the duration of the study |
| Canagliflozin (JNJ-28431754) 300 mg | EXPERIMENTAL | Each patient will receive canagliflozin (JNJ-28431754) 300 mg once daily on background standard of care for diabetes once daily for the duration of the study |
| Glimepiride | ACTIVE_COMPARATOR | Each patient will receive glimepiride, at protocol-specified doses, once daily in combination with protocol-specified doses of metformin for 104 weeks. |
| Canagliflozin + Phentermine | EXPERIMENTAL | 300 mg capsule of Canagliflozin along with 15 mg capsule of Phentermine, taken once daily, orally for 26 weeks. |
| Canagliflozin + Placebo (Phentermine) | EXPERIMENTAL | 300 mg capsule of Canagliflozin along with matching placebo to Phentermine, taken once daily, orally for 26 weeks. |
| Phentermine + Placebo (Canagliflozin) | EXPERIMENTAL | 15 mg capsule of Phentermine along with matching placebo to Canagliflozin, taken once daily, orally for 26 weeks. |
| Canagliflozin 50 mg bid | EXPERIMENTAL | Each patient will receive 50 mg canagliflozin twice daily for 18 weeks. |
| Canagliflozin 150 mg bid | EXPERIMENTAL | Each patient will receive 150 mg canagliflozin twice daily for 18 weeks |
| Canagliflozin 50 mg | EXPERIMENTAL | Each patient will receive 50 mg of canagliflozin (JNJ-28431754) once daily for 12 weeks. |
| Canagliflozin 50 mg daily | EXPERIMENTAL | Each patient will receive 50 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). |
| Canagliflozin 100 mg daily | EXPERIMENTAL | Each patient will receive 100 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). |
| Canagliflozin 200 mg daily | EXPERIMENTAL | Each patient will receive 200 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). |
| Canagliflozin 300 mg daily | EXPERIMENTAL | Each patient will receive 300 mg of canagliflozin (JNJ-28431754) once daily (in the morning) for 12 weeks with matching placebo capsule once daily (in the evening). |
| Canagliflozin 300 mg twice daily | EXPERIMENTAL | Each patient will receive 300 mg of canagliflozin (JNJ-28431754) twice daily for 12 weeks. |
| Sitagliptin 100 mg daily | ACTIVE_COMPARATOR | Each patient will receive 100 mg of sitagliptin once daily (in the morning) for 12 weeks with matching placebo once daily (in the evening). |
| Treatment Sequence ADBC | EXPERIMENTAL | Participants will receive Treatment A (1 canagliflozin tablet 100 milligram (mg) and 1 canagliflozin tablet 50 mg along with 1 Extended Release (XR) tablet of metformin 500 mg orally under fed condition) on Day 1 of treatment period 1, then Treatment D (1 XR fixed dose combination \[FDC\] tablet containing canagliflozin 150 mg and metformin 500 mg orally under fasted condition) on Day 1 of treatment period 2, then Treatment B (1 XR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed condition) on Day 1 of treatment period 3, followed by Treatment C (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg and metformin (XR) 500 mg orally under fasted condition) on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence BACD | EXPERIMENTAL | Participants will receive Treatment B on Day 1 of treatment period 1, then Treatment A on Day 1 of treatment period 2, then Treatment C on Day 1 of treatment period 3, followed by Treatment D on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence CBDA | EXPERIMENTAL | Participants will receive Treatment C Day 1 of treatment period 1, then Treatment B on Day 1 of treatment period 2, then Treatment D on Day 1 of treatment period 3, followed by Treatment A on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence DCAB | EXPERIMENTAL | Participants will receive Treatment D on Day 1 of treatment period 1, then Treatment C on Day 1 of treatment period 2, then Treatment A on Day 1 of treatment period 3, followed by Treatment B on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Canagliflozin (JNJ-28431754) | EXPERIMENTAL | Each patient will receive canagliflozin 100 mg once daily during the first 4 weeks of the 25 weeks double-blind period, then the dose may be increased to 300 mg once daily, till the end of the period. |
| Treatment Sequence ABDC | EXPERIMENTAL | Treatment A (1 immediate release (IR) fixed dose combination \[FDC\] tablet containing canagliflozin 150 milligram \[mg\] and metformin 500 mg orally under fed condition) on Day 1 of treatment period 1, followed by Treatment B (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fed condition) on Day 1 of treatment period 2, followed by Treatment D (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fasted condition) on Day 1 of treatment period 3, then Treatment C (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fasted condition) on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence BCAD | EXPERIMENTAL | Treatment B (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fed condition) on Day 1 of treatment period 1, followed by Treatment C (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fasted condition) on Day 1 of treatment period 2, followed by Treatment A (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed condition) on Day 1 of treatment period 3, then Treatment D (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fasted condition) on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence CDBA | EXPERIMENTAL | Treatment C (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fasted condition) on Day 1 of treatment period 1, followed by Treatment D (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fasted condition) on Day 1 of treatment period 2, followed by Treatment B (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fed condition) on Day 1 of treatment period 3, then Treatment A (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed condition) on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Treatment Sequence DACB | EXPERIMENTAL | Treatment D (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fasted condition) on Day 1 of treatment period 1, followed by Treatment A (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed condition) on Day 1 of treatment period 2, followed by Treatment C (1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fasted condition) on Day 1 of treatment period 3, then Treatment B (1 canagliflozin tablet 50 mg and 1 canagliflozin tablet 100 mg along with 1 IR tablet of metformin 500 mg orally under fed condition) on Day 1 of treatment period 4. A washout period of 7 days will be maintained between each treatment period. |
| Canagliflozin (Dose Group 1) | EXPERIMENTAL | Participants will receive 100 mg (as 1 x 100-mg tablet) of canagliflozin daily for 14 days. |
| Canagliflozin (Dose Group 2) | EXPERIMENTAL | Participants will be enrolled into Dose Group 2 to receive either 50 mg (as 1 x 50-mg tablet) or 300 mg (as 1 x 300-mg tablet) of canagliflozin daily for 14 days. |
| Treatment A | EXPERIMENTAL | Each participant will receive a single dose of 1 tablet of canagliflozin (CANA), 100 mg, and 4 tablets of metformin extended release (MET XR), 500 mg, administered together under fed conditions. |
| Treatment B | EXPERIMENTAL | Each participant will receive a single dose of 2 tablets of CANA/MET XR FDC, formulation 1, under fed conditions. |
| Treatment C | EXPERIMENTAL | Each participant will receive a single dose of 2 tablets of CANA/MET XR FDC, formulation 2, under fed conditions. |
| Part 1: Cana | EXPERIMENTAL | Each volunteer will receive 300 mg of canagliflozin once daily for 4 days. |
| Part 2: Sequence 1 (Dapa/Cana) | EXPERIMENTAL | Each volunteer will receive 10 mg of dapagliflozin once daily for 4 days (treatment period 1) followed by 300 mg of canagliflozin once daily for 4 days (treatment period 2). Each treatment period will be separated by a 12- to 14-day washout period (with no medication). |
| Part 2: Sequence 2 (Cana/Dapa) | EXPERIMENTAL | Each volunteer will receive 300 mg of canagliflozin once daily for 4 days (treatment period 1) followed by 10 mg of dapagliflozin once daily for 4 days (treatment period 2). Each treatment period will be separated by a 12- to 14-day washout period. |
| Treatment Sequence Group AB | EXPERIMENTAL | - |
| Treatment Sequence Group BA | EXPERIMENTAL | - |
| Treatment Sequence AB | EXPERIMENTAL | Treatment A (canaglifozin + metformin IR tablets) administered on Day 1 of Treatment Period 1 followed by Treatment B (canagliflozin/metformin IR FDC tablets) administered on Day 1 of Treatment Period 2 with a washout period of 10-15 days between treatment periods. |
| Treatment Sequence BA | EXPERIMENTAL | Treatment B (canagliflozin/metformin IR FDC tablets) administered on Day 1 of Treatment Period 1 followed by Treatment A (canaglifozin + metformin IR tablets) administered on Day 1 of Treatment Period 2 with a washout period of 10-15 days between treatment periods. |
| Canagliflozin | EXPERIMENTAL | - |
| 001 | EXPERIMENTAL | Canagliflozin/Probenecid |
| 002 | EXPERIMENTAL | Canagliflozin 300mg/Placebo Treatment B: Type=1 unit=mg number=300 form=capsule route=oral use. Capsule is taken once on Day 1 in 1 of 4 treatment periods. Form=capsule route=oral administration. Capsule is taken once on Day 2 in 1 of 4 treatment periods. |
| 003 | EXPERIMENTAL | Canagliflozin 300mg Treatment C: Type=1 unit=mg number=300 form=capsule route=oral use. Capsule is taken once daily on Day 1 and Day 2 in 1 of 4 treatment periods. |
| 004 | EXPERIMENTAL | Canagliflozin 300mg/Canagliflozin 150mg Treatment D: Type=1 unit=mg number=300 form=capsule route=oral use. Capsule is taken once on Day 1 in 1 of 4 treatment periods. Type=1 unit=mg number=150 form=capsule route=oral use. Capsule is taken once on Day 2 in 1 of 4 treatment periods. |
| Canagliflozin + cyclosporine | EXPERIMENTAL | Each volunteer will receive canagliflozin (JNJ-28431754) once daily on Days 1 through 8 with a single dose of cyclosporine on Day 7. |
| Part 1: no Intervention | NO_INTERVENTION | In Part 1 of the study, patients will not receive any study drug. |
| Part 2: canagliflozin | EXPERIMENTAL | In Part 2 of the study, patients will receive canagliflozin once daily on Days 1 through 8. |
| Canagliflozin + simvastatin | EXPERIMENTAL | Each volunteer will receive a single dose of simvastatin on Day 1, followed by canagliflozin (JNJ-28431754) once daily on Days 2 through 6. On Day 7 volunteers will receive a single dose of simvastatin in combination with a single dose of canagliflozin. |
| Canagliflozin (JNJ-28431754) + glyburide | EXPERIMENTAL | Each volunteer will receive a single dose of glyburide on Day 1, followed by canagliflozin (JNJ-28431754) once daily on Days 4 through 8. On Day 9 volunteers will receive a single dose of glyburide in combination with a single dose of canagliflozin. |
| Sequence 1 (ADBC) | EXPERIMENTAL | Each volunteer will receive Treatment A on Day 1 of Treatment Period 1, followed by Treatment D on Day 1 of Treatment Period 2, followed by Teatment B on Day 1 of Treatment Period 3, and followed by Treatment C on Day 1 of Treatment Period 4. Each treatment period will be 2 days in duration and there will be a washout period (with no medication) of 10 to 14 days between each treatment period. |
| Sequence 2 (BACD) | EXPERIMENTAL | Each volunteer will receive Treatment B on Day 1 of Treatment Period 1, followed by Treatment A on Day 1 of Treatment Period 2, followed by Treatment C on Day 1 of Treatment Period 3, and followed by Treatment D on Day 1 of Treatment Period 4. Each treatment period will be 2 days in duration and there will be a washout period (with no medication) of 10 to 14 days between each treatment period. |
| Sequence 3 (CBDA) | EXPERIMENTAL | Each volunteer will receive Treatment C on Day 1 of Treatment Period 1, followed by Treatment B on Day 1 of Treatment Period 2, followed by Treatment D on Day 1 of Treatment Period 3, and followed by Treatment A on Day 1 of Treatment Period 4. Each treatment period will be 2 days in duration and there will be a washout period (with no medication) of 10 to 14 days between each treatment period. |
| Sequence 4 (DCAB) | EXPERIMENTAL | Each volunteer will receive Treatment D on Day 1 of Treatment Period 1, followed by Treatment C on Day 1 of Treatment Period 2, followed by Treatment A on Day 1 of Treatment Period 3, and followed by Treatment B on Day 1 of Treatment Period 4. Each treatment period will be 2 days in duration and there will be a washout period (with no medication) of 10 to 14 days between each treatment period. |
| Group 1 (normal kidney function) | EXPERIMENTAL | Each volunteer will receive a single dose of canagliflozin (JNJ-28431754) on Day 1 |
| Group 2 (mild kidney impairment) | EXPERIMENTAL | Each volunteer will receive a single dose of canagliflozin (JNJ-28431754) on Day 1 |
| Group 3 (moderate kidney impairment) | EXPERIMENTAL | Each volunteer will receive a single dose of canagliflozin (JNJ-28431754) on Day 1 |
| Group 4 (severe kidney impairment) | EXPERIMENTAL | Each volunteer will receive a single dose of canagliflozin (JNJ-28431754) on Day 1 |
| Group 5 (hemodialysis) | EXPERIMENTAL | Each volunteer will receive a single dose of canagliflozin (JNJ-28431754) on Day 1 following completion of hemodialysis. Approximately 10 days later, each volunteer will receive another single dose of canagliflozin before hemodialysis begins. |
| Canagliflozin + oral contraceptive | EXPERIMENTAL | Each volunteer will receive a single dose of an oral contraceptive containing ethinyl estradiol and levonorgestrel on Day 1, followed by canagliflozin (JNJ-28431754) once daily on Days 4 through 8. On Day 9 volunteers will receive a single dose of an oral contraceptive containing ethinyl estradiol and levonorgestrel in combination with a single dose of canagliflozin. |
| Metformin + canagliflozin (JNJ-28431754) | EXPERIMENTAL | Each volunteer will receive a single dose of metformin on Day 1 followed by canagliflozin (JNJ-28431754) once daily on Days 4 to 7. On Day 8, volunteers will receive a single dose of canagliflozin in combination with a single dose of metformin. |
| Cohort 1 | EXPERIMENTAL | Each volunteer will receive a total daily dose of 30 mg of canagliflozin (JNJ-28431754) or placebo (inactive medication) on Days 1 through 14. |
| Cohort 2 | EXPERIMENTAL | Each volunteer will receive a total daily dose of 100 mg of canagliflozin (JNJ-28431754) or placebo (inactive medication) on Days 1 through 14. |
| Cohort 3 | EXPERIMENTAL | Each volunteer will receive a total daily dose of 300 mg of canagliflozin (JNJ-28431754) or placebo (inactive medication) on Days 1 through 14. |
| Cohort 4 | EXPERIMENTAL | Each volunteer will receive a total daily dose of 600 mg of canagliflozin (JNJ-28431754) or placebo (inactive medication) on Days 1 through 14. |
| Cohort 5 | EXPERIMENTAL | Each volunteer will receive 300 mg of canagliflozin (JNJ-28431754) twice daily (600 mg total daily dose) or placebo (inactive medication) twice daily on Days 1 through 14. |
| Name | Type | Description |
|---|---|---|
| Canagliflozin 100 mg | DRUG | Participants will receive 100 mg immediate-release, over-encapsulated tablets (as a capsule) orally once daily. |
| Placebo | DRUG | Participants will receive matching placebo capsules orally once daily. |
| Canagliflozin 300 mg | DRUG | Canagliflozin 300 mg tablet will be administered orally once-daily. |
| Canagliflozin | DRUG | One 100 mg over-encapsulated tablet orally once daily |
| Metformin XR | DRUG | One 500 mg tablet (Day 1 up to week 1); two 500 mg tablets (Week 1 up to Week 3); three 500 mg tablets (Week 3 to Week 6); four 500 mg tablets (Week 6 to Week 9). Tablets will be administered with the evening meal. |
| Canagliflozin 100mg | DRUG | Type=1, unit=mg, number=100, form=capsule, route=oral use. One capsule once daily for up to 18 weeks after completing a single-blind placebo run-in period (1 placebo capsule once daily for up to 2 weeks). |
| Canagliflozin 300mg | DRUG | Type=1, unit=mg, number=300, form=capsule, route=oral use. One capsule once daily for up to 18 weeks after completing a single-blind placebo run-in period (1 placebo capsule once daily for up to 2 weeks). |
| Metformin | DRUG | The participant's stable dose of background therapy of metformin should be continued throughout the study. |
| Sulphonylurea | DRUG | The participant's stable dose of background therapy of metformin plus sulphonylurea should be continued throughout the study. |
| Sitagliptin 100 mg | DRUG | One 100 mg capsule once daily for 52 weeks with protocol-specified doses of metformin and sulphonylurea |
| Sitagliptin | DRUG | One 100 mg over-encapsulated tablet orally once daily beginning at Week 26 until Week 52 with stable doses of metformin and pioglitazone. |
| Pioglitazone | DRUG | The patient's stable dose of pioglitazone background therapy should be continued throughout the study. |
| Antihyperglycemic agent(s) | DRUG | Stable doses of antihyperglycemic agents (sulfonylurea agent, thiazolidinediones, dipeptidyl peptidase 4 \[DPP-4\] inhibitors, metformin, insulin \[all types\]) and their combinations (sulfonylurea agent and insulin \[all types\], metformin and insulin \[all types\], metformin and sulfonylurea, alpha glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase 4 \[DPP-4\]) are used as per protocol specifications. |
| Sulphonylruea | DRUG | The patient's stable dose of background sulphonylurea therapy should be continued throughout the study. |
| Metformin immediate release | DRUG | The patient's stable dose of metformin immediate release background therapy should be continued throughout the study. |
| Canagliflozin (JNJ-28431754) 100 mg | DRUG | One 100 mg capsule taken orally (by mouth) once daily |
| Canagliflozin (JNJ-28431754) 300 mg | DRUG | One 300 mg capsule taken orally (by mouth) once daily |
| Glimepiride | DRUG | Glimepiride will be given orally (by mouth), as over-encapsulated tablets, starting at a dose of 1mg once daily and increasing to a maximum of 6 mg or 8 mg once daily for 104 weeks. |
| Canagliflozin (JNJ-28431754) | DRUG | Canagliflozin (JNJ-28431754) will be given orally as over-encapsulated tablets, at a dose of 100 mg or 300 mg once daily for 104 weeks. |
| Phentermine | DRUG | 15 mg capsule, taken once daily, orally for 26 weeks. |
| Matching Placebo to Canagliflozin | DRUG | Placebo capsules look like canagliflozin but do not contain any active drug, taken once daily, orally for 26 weeks. |
| Matching Placebo to Phentermine | DRUG | Placebo capsules look like phentermine but do not contain any active drug, taken once daily, orally for 26 weeks. |
| Canagliflozin 50 mg | DRUG | One canagliflozin 50-mg capsule taken orally twice daily with a meal for 18 weeks |
| Canagliflozin 150 mg | DRUG | 1 canagliflozin 150-mg capsule taken orally twice daily with a meal for 18 weeks |
| Canagliflozin and Metformin Extended Release (XR) Fixed Dose Combination [FDC] | DRUG | Participants will receive 1 XR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed (Treatment B)or fasted condition (Treatment D) in a given treatment period as per treatment sequence. |
| Metformin Extended Release (XR) | DRUG | Participants will receive metformin XR 500 mg tablet orally under fed (part of Treatment A) or fasted condition (part of Treatment C) in a given treatment period as per treatment sequence. |
| Canagliflozin, 100 mg | DRUG | One 100 mg capsule taken orally (by mouth) once daily |
| Canagliflozin, 300 mg | DRUG | One 300 mg capsule taken orally (by mouth) once daily |
| Canagliflozin and Metformin Immediate Release (IR) Fixed Dose Combination [FDC] | DRUG | Participants will receive 1 IR FDC tablet containing canagliflozin 150 mg and metformin 500 mg orally under fed or fasted condition in each treatment period as per treatment sequence. |
| Canagliflozin + Metformin Immediate Release (IR) Fixed Dose Combination (FDC) | DRUG | Canagliflozin and metformin IR FDC tablet 50 mg/500 mg orally under fed or fasted conditions on Day 1 of any of the 4 treatment periods. |
| Metformin IR | DRUG | Metformin IR tablet 500 mg orally under fed or fasted conditions on Day 1 of any of the 4 treatment periods. |
| Metformin XR, 500 mg | DRUG | Each tablet contains metformin extended release (MET XR), 500 mg, to be taken orally (by mouth). |
| CANA/MET XR FDC, Formulation 1, 50 mg/1000 mg | DRUG | Each tablet contains 50 mg of canagliflozin and 1000 mg of metformin HCl granulate, formulation 1, to be taken orally. |
| CANA/MET XR FDC, Formulation 2, 50 mg/1000 mg | DRUG | Each tablet contains 50 mg of canagliflozin and 1000 mg of metformin HCl granulate, formulation 2, to be taken orally. |
| CANA/MET XR FDC, Formulation 1, 50 mg/500 mg | DRUG | Each tablet contains 50 mg of canagliflozin and 500 mg of metformin HCl granulate, formulation 1, in release-controlling polymers to obtain the XR granulation, to be taken orally. |
| CANA/MET XR FDC, Formulation 2, 50 mg/500 mg | DRUG | Each tablet contains 50 mg of canagliflozin and 500 mg of metformin HCl granulate, formulation 2, in release-controlling polymers to obtain the XR granulation, to be taken orally. |
| CANA/MET XR FDC, Formulation 1, 150 mg/1,000 mg | DRUG | Each tablet contains 150 mg of canagliflozin and 1,000 mg of metformin HCl granulate formulation 1, in release-controlling polymers to obtain the XR granulation, to be taken orally. |
| CANA/MET XR FDC, Formulation 2, 150 mg/1,000 mg | DRUG | Each tablet contains 150 mg of canagliflozin and 1,000 mg of metformin HCl granulate formulation 2, in release-controlling polymers to obtain the XR granulation, to be taken orally. |
| CANA/MET XR FDC, Formulation 1, 150 mg/500 | DRUG | Each tablet contains 150 mg of canagliflozin and 500 mg of metformin HCl granulate, formulation 1, to be taken orally. |
| CANA/MET XR FDC, Formulation 2, 150 mg/500 mg | DRUG | Each tablet contains 150 mg of canagliflozin and 500 mg of metformin HCl granulate, formulation 2, to be taken orally. |
| Dapagliflozin | DRUG | One 10 mg over-encapsulated tablet taken orally once daily for 4 days during Part 2 (Sequence 1 \[treatment period 1\] or Sequence 2 \[treatment period 2\]). |
| Somatostatin | DRUG | A primed (50 mcg in 1 mL sterile 0.9% NaCl solution i.v. injection over 1 minute) constant (500 mcg/hour) i.v. infusion of somatostatin for 4 hours approximately 2 hours after canagliflozin or placebo dosing on Day 1 of Treatment Period 1 and Day 1 of Treatment Period 2. The total dose of somatostatin administered during each period will be 50 mcg + 500 mcg/hour x 4 hours = 2050 mcg. |
| C-peptide | DRUG | Single bolus dose of 150 mcg synthetic human C-peptide in 1 mL water for injection administered i.v. (in the vein) approximately 3 hours after canagliflozin or placebo dosing on Day 1 of Treatment Period 1 and Day 1 of Treatment Period 2. |
| Canagliflozin tablets | DRUG | Type = exact number, unit = mg, number = 100, form = tablet, route = oral use. One canagliflozin tablet taken orally (by mouth) on Day 1 of Treatment Period 1. |
| Metformin IR tablets | DRUG | Type = exact number, unit = mg, number = 500, form = tablet, route = oral use. Two metformin IR tablets taken orally (by mouth) on Day 1 of Treatment Period 1. |
| Canagliflozin/metformin IR FDC tablets | DRUG | Type = exact number, unit = mg, number = 50/500, form = tablet, route = oral use. Two Canagliflozin/metformin IR FDC tablets taken orally on Day 1 of Treatment Period 2. |
| Canagliflozin/Probenecid | DRUG | Canagliflozin: Type = 1, unit = mg, number = 300, form = tablet, route = oral use. Probenicid: Type = 1, unit = mg, number = 500, form = tablet, route = oral use. One 300-mg canagliflozin tablet taken orally once daily on Days 1 to 14 (administration of canagliflozin alone) and on Days 15 to 17 (administration of canagliflozin + twice-daily administration of probenecid). |
| Rifampin | DRUG | Type=2, unit=mg, number=300, Form=capsule, route=oral use. Two 300-mg capsules once daily on days Days 4 through 12. |
| Canagliflozin 300mg/Placebo | DRUG | Treatment B: Type=1, unit=mg, number=300, form=capsule, route=oral use. Capsule is taken once on Day 1 in 1 of 4 treatment periods. Form=capsule, route=oral administration. Capsule is taken once on Day 2 in 1 of 4 treatment periods. |
| Canagliflozin 300mg/Canagliflozin 150mg | DRUG | Treatment D: Type=1, unit=mg, number=300, form=capsule, route=oral use. Capsule is taken once on Day 1 in 1 of 4 treatment periods. Type=1, unit=mg, number=150, form=capsule, route=oral use. Capsule is taken once on Day 2 in 1 of 4 treatment periods. |
| Canagliflozin, 50 mg | DRUG | Type=1, unit=mg, number=50, form=tablet, route=oral use.Tablet is taken once without food during 1 of 3 treatment periods. |
| Cyclosporine | DRUG | Four 100 mg capsules (400 mg total dose) taken orally 30 minutes before the last dose of canagliflozin (JNJ-28431754) on Day 8. |
| Canagliflozin/Metformin | DRUG | Two 1000-mg tablets of metformin on Day 1 followed by one 300-mg tablet of canagliflozin once daily on Days 4 through 8, followed by two 1000-mg tablets of metformin and one 300-mg tablet of canagliflozin on Day 8. |
| Canagliflozin/Warfarin | DRUG | Treatment A: Tablets, oral, canagliflozin 300 mg, once daily for 12 days and canagliflozin 300 mg + warfarin 30 mg, single dose on Day 6 followed 14 days later by Treatment B: Tablets, oral, warfarin 30 mg, single dose on Day 1 |
| Digoxin 0.5 mg | DRUG | Two 0.25 mg tablets (0.5 mg total dose) taken orally (by mouth) on Day 1. |
| Digoxin 0.25 mg | DRUG | One 0.25 mg tablet taken orally on Days 2 through 7. |
| Simvastatin | DRUG | One 40 mg tablet taken orally (by mouth) on Day 1 and Day 7. |
| Canagliflozin (JNJ-28431754) 200 mg | DRUG | One 200 mg tablet taken orally (by mouth) on Day 1. |
| Glyburide | DRUG | One 1.25 mg tablet taken orally (by mouth) on Day 1 and Day 9. |
| Moxifloxacin | DRUG | One 400 mg over-encapsulated tablet of moxifloxacin taken orally (by mouth) on Day 1 of Treatment D. |
| Oral contraceptive | DRUG | One tablet (0.150 mg of levonorgestrel and 0.030 mg of ethinyl estradiol) taken orally (by mouth) on Day 1 and Day 9. |
Inclusion Criteria: \- Have clinically stable symptomatic heart failure (HF) (heart failure with reduced ejection fraction \[HFrEF\] and heart failure with preserved ejection fraction \[HFpEF\]): (A) For HFrEF: (a) ejection fraction (EF) less than or equal to (\<=) 40 percent (%) and (b) a primary ...
Canagliflozin is a small molecule drug developed by Johnson & Johnson (ticker JNJ). It has been studied in type 1 and type 2 diabetes mellitus, heart failure, and bioequivalence studies in healthy volunteers. It is also known by the code JNJ-28431754 and is available in tablet forms, including fixed-dose combinations with metformin.
Canagliflozin targets SLC5A2, also known as sodium-glucose cotransporter 2 (SGLT2). It acts as an inhibitor of this transporter. By inhibiting SLC5A2, canagliflozin reduces renal glucose reabsorption, which lowers blood glucose levels in patients with diabetes.
Canagliflozin is developed by Johnson & Johnson, which trades under the ticker symbol JNJ. The company has sponsored clinical trials of canagliflozin both as a single agent and in fixed-dose combinations with metformin.
Canagliflozin is in Phase 1 development according to the available data. It has been investigated in 29 completed clinical trials, with no active trials currently listed. The trials include Phase 1 bioequivalence studies and Phase 3 studies in type 2 diabetes and heart failure.
Canagliflozin has been studied in completed trials including NCT04252287, a Phase 3 study in heart failure, and NCT03170518, a Phase 3 study in children and adolescents with type 2 diabetes. Phase 1 bioequivalence trials include NCT02865668 and NCT02851212, which assessed fixed-dose combinations with metformin.
Yes, canagliflozin is also known by the code JNJ-28431754. Other alternative names include canagliflozin tablets and various fixed-dose combinations with metformin, such as canagliflozin and metformin immediate release or extended release. These refer to the same active ingredient, canagliflozin.