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NCT01032629: CANVAS

CANVAS - CANagliflozin cardioVascular Assessment Study

Completed Phase 3 Results posted Last updated 7 December 2018
What this trial tests

Phase 3 trial testing Placebo in Diabetes Mellitus, Type 2 in 4,330 participants. Completed in 22 February 2017.

Timeline
9 December 2009
Primary endpoint
22 February 2017
22 February 2017

Quick facts

Lead sponsorJanssen Research & Development, LLC
PhasePhase 3
StatusCompleted
Study typeINTERVENTIONAL
Allocationrandomized
Designparallel
Maskingquadruple
Primary purposetreatment
Enrollment4,330
Start date9 December 2009
Primary completion22 February 2017
Estimated completion22 February 2017
Sites305 locations across Colombia, Malaysia, Poland, New Zealand, Netherlands, Russia, Belgium, Sweden

Drugs / interventions tested

Conditions studied

Sponsor

Janssen Research & Development, LLC — full company profile →

Who can join

30 and older, any sex, with Diabetes Mellitus, Type 2 or Cardiovascular Diseases. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

Major Adverse Cardiovascular Events (MACE) Composite of Cardiovascular (CV) Death, Non-Fatal Myocardial Infarction (MI), and Non-Fatal Stroke Primary · Up to approximately 8 years

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.

GroupValue95% CI
Placebo30.36
Canagliflozin 100 mg28.41
Canagliflozin 300 mg25.37
Canagliflozin (Total)26.89
Change From Baseline in Homeostasis Model Assessment 2 Steady-State Beta-Cell Function (HOMA2-%B) at the End-of-Treatment (EOT) Secondary · Baseline and end of treatment (approximately 338 weeks)

The homeostatic model assessment (HOMA) quantifies insulin resistance and beta-cell function. HOMA2-%B is a computer model that uses fasting plasma insulin and glucose concentrations to estimate steady-state beta cell function (%B) as a percentage of a normal reference population (normal young adults). The normal reference population was set at 100 percent.

GroupValue95% CI
Placebo4.02± 1.611
Canagliflozin 100 mg6.82± 1.533
Canagliflozin 300 mg8.09± 1.587
Percentage of Participants With Progression of Albuminuria at the End-of-Treatment Secondary · End of treatment (approximately 338 weeks)

Progression defined as the development of micro-albuminuria (albumin/creatinine ratio (ACR) greater than or equal to \[\>=\] 30 milligram per gram (mg/g) and less than or equal to \<= 300 mg/g) or macroalbuminuria (ACR of \>300 mg/g) in a participant with baseline normoalbuminuria or the development of macro-albuminuria in a participant with baseline microalbuminuria. Percentage of participants with progression of albuminuria at the end-of-treatment were assessed.

GroupValue95% CI
Placebo24.0
Canagliflozin 100 mg20.2
Canagliflozin 300 mg18.3
Change From Baseline in Proinsulin/Insulin (PI/I) Ratio at the End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

A raised proinsulin-to-insulin ratio due to impaired processing of proinsulin is an early marker of beta cell dysfunction. Beta-cell dysfunction was evaluated by calculating the PI/I ratio, which estimates the capacity of beta cells to convert proinsulin to insulin and may represent an acceptable method to indicate the degree of beta-cell secretion.

GroupValue95% CI
Placebo0.70± 0.150
Canagliflozin 100 mg0.67± 0.140
Canagliflozin 300 mg1.03± 0.142
Change From Baseline in Urinary Albumin/Creatinine Ratio at End-of-Treatment Secondary · Baseline and End of treatment (approximately 338 weeks)

Urinary Albumin/Creatinine Ratio is a potential marker of chronic kidney disease, calculated as a ratio of Urinary Albumin and Urinary Creatinine.

GroupValue95% CI
Placebo29.3027.66 – 31.03
Canagliflozin 100 mg25.5024.09 – 27
Canagliflozin 300 mg24.4723.11 – 25.91
Change From Baseline in Estimated Glomerular Filtration Rate (eGFR) at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in Estimated Glomerular Filtration Rate (eGFR) was assessed at end of treatment. GFR is a measure of the rate at which blood is filtered by the kidney. Modification of Diet in Renal Disease (MDRD) is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and sex. eGFR milliliters/minute/1.73 meters square (mL/min/1.73 m\^2) = 175 \* (serum creatinine) \^ 1.154 \* (Age) \^-0.203 \*(0.742 if female) \* (1.21 if Black).

GroupValue95% CI
Placebo-5.23± 0.390
Canagliflozin 100 mg-3.55± 0.388
Canagliflozin 300 mg-3.98± 0.392
Change From Baseline in Glycated Hemoglobin (HbA1c) at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in glycated hemoglobin (HbA1c) percentage (%) was assessed at end of treatment. Glycated hemoglobin is a form of hemoglobin that is measured primarily to identify the average glucose concentration in the blood.

GroupValue95% CI
Placebo0.01± 0.032
Canagliflozin 100 mg-0.26± 0.032
Canagliflozin 300 mg-0.31± 0.032
Change From Baseline in Fasting Plasma Glucose (FPG) Levels at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in the fasting plasma glucose levels at end-of-treatment was assessed.

GroupValue95% CI
Placebo0.16± 0.076
Canagliflozin 100 mg-0.42± 0.075
Canagliflozin 300 mg-0.57± 0.076
Percent Change From Baseline in Body Weight at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Percent change from baseline in body weight was assessed at the end of treatment.

GroupValue95% CI
Placebo-0.50± 0.184
Canagliflozin 100 mg-3.47± 0.183
Canagliflozin 300 mg-4.12± 0.185
Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in systolic blood pressure and diastolic blood pressure was assessed.

SBP(Change at end of treatment)
GroupValue95% CI
Placebo-1.96± 0.377
Canagliflozin 100 mg-4.91± 0.375
Canagliflozin 300 mg-6.49± 0.378
DBP (Change at end of treatment)
GroupValue95% CI
Placebo-2.88± 0.223
Canagliflozin 100 mg-3.70± 0.221
Canagliflozin 300 mg-4.51± 0.223
Change From Baseline in Triglycerides Levels at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in triglycerides levels was assessed.

GroupValue95% CI
Placebo0.05± 1.597
Canagliflozin 100 mg0.13± 1.679
Canagliflozin 300 mg0.09± 1.238
Change From Baseline in Cholesterol, High-Density Lipoprotein Cholesterol (HDL-C) and Low Density Lipoprotein Cholesterol (LDL-C) Levels at End-of-Treatment Secondary · Baseline and end of treatment (approximately 338 weeks)

Change from baseline in cholesterol, high-density lipoprotein cholesterol and low density lipoprotein cholesterol levels were assessed.

Cholesterol (change at EOT)
GroupValue95% CI
Placebo-0.07± 0.028
Canagliflozin 100 mg0.11± 0.027
Canagliflozin 300 mg0.16± 0.028
HDL-C (change at EOT)
GroupValue95% CI
Placebo-0.01± 0.006
Canagliflozin 100 mg0.04± 0.006
Canagliflozin 300 mg0.05± 0.006
LDL-C (change at EOT)
GroupValue95% CI
Placebo-0.07± 0.022
Canagliflozin 100 mg0.04± 0.022
Canagliflozin 300 mg0.10± 0.023

Adverse events — posted to ClinicalTrials.gov

Time frame: Approximately 8 years. Reporting threshold: 2%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

Placebo
Serious: 584/1441 (41%)
Deaths: 74/1441
Canagliflozin 100 mg
Serious: 601/1445 (42%)
Deaths: 68/1445
Canagliflozin 300 mg
Serious: 606/1441 (42%)
Deaths: 66/1441

Serious adverse events (948 terms)

ReactionSystemPlaceboCanagliflozin 100 mgCanagliflozin 300 mg
PneumoniaInfections and infestations
Angina PectorisCardiac disorders
OsteoarthritisMusculoskeletal and connective tissue disorders
Angina UnstableCardiac disorders
Atrial FibrillationCardiac disorders
Chest PainGeneral disorders
Coronary Artery DiseaseCardiac disorders
Cardiac FailureCardiac disorders
Cardiac Failure CongestiveCardiac disorders
CellulitisInfections and infestations
Myocardial InfarctionCardiac disorders
Urinary Tract InfectionInfections and infestations
Transient Ischaemic AttackNervous system disorders
GangreneInfections and infestations
Acute Kidney InjuryRenal and urinary disorders
Benign Prostatic HyperplasiaReproductive system and breast disorders
Skin UlcerSkin and subcutaneous tissue disorders
Cerebrovascular AccidentNervous system disorders
OsteomyelitisInfections and infestations
SepsisInfections and infestations
HypoglycaemiaMetabolism and nutrition disorders
Peripheral Arterial Occlusive DiseaseVascular disorders
Myocardial IschaemiaCardiac disorders
CholelithiasisHepatobiliary disorders
Carotid Artery StenosisNervous system disorders
Other adverse events (77 terms — click to expand)

ReactionSystemPlaceboCanagliflozin 100 mgCanagliflozin 300 mg
NasopharyngitisInfections and infestations
HypoglycaemiaMetabolism and nutrition disorders
Upper Respiratory Tract InfectionInfections and infestations
Urinary Tract InfectionInfections and infestations
Back PainMusculoskeletal and connective tissue disorders
DiarrhoeaGastrointestinal disorders
ArthralgiaMusculoskeletal and connective tissue disorders
BronchitisInfections and infestations
HypertensionVascular disorders
HeadacheNervous system disorders
Pain in ExtremityMusculoskeletal and connective tissue disorders
CoughRespiratory, thoracic and mediastinal disorders
InfluenzaInfections and infestations
BalanoposthitisReproductive system and breast disorders
CataractEye disorders
HyperglycaemiaMetabolism and nutrition disorders
Oedema PeripheralGeneral disorders
PollakiuriaRenal and urinary disorders
OsteoarthritisMusculoskeletal and connective tissue disorders
ConstipationGastrointestinal disorders
Musculoskeletal PainMusculoskeletal and connective tissue disorders
SinusitisInfections and infestations
Chest PainGeneral disorders
DizzinessNervous system disorders
NauseaGastrointestinal disorders
FatigueGeneral disorders
AnaemiaBlood and lymphatic system disorders
VertigoEar and labyrinth disorders
GastroenteritisInfections and infestations
HypotensionVascular disorders
Muscle SpasmsMusculoskeletal and connective tissue disorders
Skin UlcerSkin and subcutaneous tissue disorders
Diabetic RetinopathyEye disorders
MyalgiaMusculoskeletal and connective tissue disorders
Abdominal PainGastrointestinal disorders
PyrexiaGeneral disorders
DyspnoeaRespiratory, thoracic and mediastinal disorders
DyspepsiaGastrointestinal disorders
Gastrooesophageal Reflux DiseaseGastrointestinal disorders
RashSkin and subcutaneous tissue disorders

Most-reported serious reactions: Pneumonia, Angina Pectoris, Osteoarthritis, Angina Unstable, Atrial Fibrillation, Chest Pain, Coronary Artery Disease, Cardiac Failure.

Data from ClinicalTrials.gov NCT01032629 adverse events section.

Sponsor's own description

The study will assess canagliflozin (JNJ-28431754) in the treatment of patients with type 2 diabetes mellitus (T2DM) with regard to cardiovascular (CV) risk for major adverse cardiac events (MACE). Other objectives include evaluating the overall safety, tolerability, and effectiveness of canagliflozin. The data from this study will be combined with the data from CANVAS-R study (Study of the Effects of Canagliflozin on Renal Endpoints in Adult Subjects with T2DM, NCT01989754) in a pre-specified integrated analysis of CV safety outcomes to satisfy US FDA post-marketing requirements for canagliflozin.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

  1. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes.
    Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, et al · · 2017 · cited 5227× · PMID 28605608 · DOI 10.1056/nejmoa1611925
  2. Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future.
    Kahn SE, Cooper ME, Del Prato S. · · 2014 · cited 1100× · PMID 24315620 · DOI 10.1016/s0140-6736(13)62154-6
  3. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus - Mechanisms, Management, and Clinical Considerations.
    Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. · · 2016 · cited 782× · PMID 27297342 · DOI 10.1161/circulationaha.116.022194
  4. Inflammation and atherosclerosis: signaling pathways and therapeutic intervention.
    Kong P, Cui ZY, Huang XF, Zhang DD, et al · · 2022 · cited 749× · PMID 35459215 · DOI 10.1038/s41392-022-00955-7
  5. Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering Drugs: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors).
    Kosiborod M, Cavender MA, Fu AZ, Wilding JP, et al · · 2017 · cited 578× · PMID 28522450 · DOI 10.1161/circulationaha.117.029190
  6. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials.
    Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, et al · · 2018 · cited 464× · PMID 29937267 · DOI 10.1016/s2213-8587(18)30141-4
  7. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition.
    Vallon V, Thomson SC. · · 2017 · cited 435× · PMID 27878313 · DOI 10.1007/s00125-016-4157-3
  8. Diabetic vascular diseases: molecular mechanisms and therapeutic strategies.
    Li Y, Liu Y, Liu S, Gao M, et al · · 2023 · cited 392× · PMID 37037849 · DOI 10.1038/s41392-023-01400-z

Verify or expand the search:

Other recruiting trials for Diabetes Mellitus, Type 2

Currently open trials in the same condition.

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Primary sources · FDA · ClinicalTrials.gov · EMA · SEC EDGAR · ChEMBL · Wikidata · full sourcing