Two Comprehensive and Conclusive Clinical Trials Found That Invokana Increases the Risk of Amputations
May 16, 2017 – The U.S. Food and Drug Administration released a Drug Safety Communication stating, “FDA confirms increased risk of leg and foot amputations with diabetes medicine canagliflozin (Invokana, Invokamet, and Invokamet XR).” The two clinical trials on which the U.S. Food and Drug Administration based their decision to require new Invokana drug warning labels on the drug’s packaging are the CANVAS and CANVAS-R studies.
CANVAS*
Canagliflozin Cardiovascular Assessment Study
The CANVAS study was sponsored by Janssen Research & Development, LLC and in collaboration with the George Institute for Global Health, Australia. All information was provided by Janssen Research & Development, LLC. The study was started on December 9, 2009, and concluded on February 22, 2017.
Study Goal
The goal of the CANVAS study was to:
- Assess the overall tolerability, safety, and effectiveness of the drug canagliflozin with patients who have type 2 diabetes mellitus (T2DM)
- Determine if there is an increased cardiovascular (CV) risk for major adverse cardiac events (MACE)
- Combine the data from the CANVAS-R study to meet the U.S. Food and Drug Administration’s post-marketing requirements.
Study Description
The CANVAS study compared the drug canagliflozin with a placebo (a non-treatment) to determine if there were any increases in cardiovascular events such as cardiovascular death, heart attacks, or strokes in patients given canagliflozin and whose diabetes was not under control at the start of the study and had a medical history including cardiovascular events or a high risk for sustaining a cardiovascular event.
The CANVAS study also included three sub-studies that compared canagliflozin’s effectiveness in reducing blood glucose as compared to patients receiving other specific and commonly-used diabetes agents. The CANVAS study also assessed whether canagliflozin was as relatively safe as a placebo or commonly-used diabetes agent.
Study Design
In the CANVAS study, 4,330 participants were randomly assigned to a treatment plan. Treatment Plan “A” that consisted of 1 of 2 doses of canagliflozin (100 or 300 mg). Treatment Plan “B” consisted of a placebo (dummy treatment). The study was to be conducted for approximately nine years. The study reached its completion date in February 2017.
Eligibility Criteria
Inclusionary Criteria: Both males and females participated in the study. To meet the eligibility requirements of the study participants had to be at least 30 years old. Participants needed a type 2 diabetes mellitus diagnosis and a history of a previous cardiovascular (CV) event. Participants were required to have inadequate control of their diabetes and (1) not currently taking any diabetes drug therapy or (2) receiving treatment of a pre-approved class of diabetic drugs.
Exclusionary Criteria: Any potential participant with a history of the following were excluded from participating in the study: Diabetic ketoacidosis
- Type 1 diabetes
- Pancreas or beta-cell transplantation
- Diabetes secondary to pancreatitis
- Diabetes secondary to pancreatectomy
- 1 or more hypoglycemic episodes six months before the study’s eligibility screening.
You can read more information, and the study’s published data can be found, here in CANVAS Study.
CANVAS-R*
“A Study of the Effects of Canagliflozin on Renal Endpoints in Adult Participants with Type 2 Diabetes Mellitus.”
The CANVAS-R study was a study initiated on January 16, 2014, and sponsored by Janssen Research & Development, LLC. The study was performed in collaboration with the George Institute for Global Health, Australia. Janssen Research & Development, LLC was responsible for providing the results, data, and information from the CANVAS-R study. The study concluded on February 23, 2017.
Study Goal
The goal of the CANVAS-R Study was to determine the effect of the drug canagliflozin as compared to placebo on a progression of albuminuria in participants with Type 2 Diabetes Mellitus receiving standard care, but with inadequate glycemic control and at elevated risk of cardiovascular events. There were 5813 participants in the assessment study which concluded in February of 2017.
Study Description
The CANVAS-R study was conducted in adult participants over the age of 30. The participants were both male and female who were diagnosed with Type 2 Diabetes Mellitus (T2DM). The participants included in the study were screened in order to ensure that they also were receiving treatment for hyperglycemia and either had cardiovascular (CV) risk factors or a history of a prior cardiovascular event, or they had 2 or more risk factors for a cardiovascular event.
Participants in the CANVAS-R study were randomly assigned using the 1:1 ratio of canagliflozin and a matching placebo which was taken once daily. Canagliflozin was given to the test participants at a dose of 100 mg/day from week 1 to Week 13. The dose of canagliflozin could be increased to as much as 300mg/day under the supervision and discretion of the study’s investigator if the study’s participant required additional glycemic control and the study’s participant was tolerating the 100mg dose of canagliflozin.
The CANVAS-R study consisted of a 2-week screening period which was performed using a “double-blind” treatment period. This period lasted between 78 and 156 weeks. The completion of the study occurred when the last study participant randomized received a 78 week of follow-up or when there with a total of 688 major adverse cardiovascular (CV) events total from the CANVAS and CANVAS-R studies.
Study Design
In the CANVAS-R study, 5,812 eligible participants were recruited at 422 sites in 24 countries. Participants were randomly assigned in a 1:1 ratio either to a canagliflozin or a placebo testing group. The study was conducted using a “double-blind” treatment period of about 80 weeks. The randomized testing period lasted for two weeks. Treatment Plan “A” consisted of a 100 mg dose of canagliflozin (which could be increased to a maxim 300 mg dose per day). Treatment Plan “B” consisted of a placebo. The study recruited participants between January 2014 and May 2015, and reached its completion date in February 2017.
Eligibility Criteria
Inclusionary Criteria: Both males and females participated in the study. All participants in the CANVAS-R study had to be a minimum of 30 years of age. The participants needed to be diagnosed with type 2 diabetes mellitus and have a history of a previous cardiovascular (CV) event or have 2 or more cardiovascular risk factors. In addition, participants could not be receiving antihyperglycemic agents (AHA) therapy, or be taking an AHA monotherapy, or a combination AHA therapy with any approved agent for the control of blood glucose levels.
Exclusionary Criteria: Any potential participant was excluded with a history of: Diabetic ketoacidosis
- Type 1 diabetes
- Pancreas or beta-cell transplantation
- Diabetes secondary to pancreatitis
- Diabetes secondary to pancreatectomy
- 1 or more hypoglycemic episodes six months before the study’s eligibility screening.
- History of hereditary glucose-galactose malabsorption or primary renal glycosuria
- Ongoing, inadequately controlled thyroid disorder
- Renal disease that required treatment with immunosuppressive therapy or a history of chronic dialysis or renal transplant
- Myocardial infarction, unstable angina, revascularization procedure, or cerebrovascular accident within three months before screening.
You can read more information, and the study’s published data can be found at CANVAS-R.
*Please Note: The following canagliflozin studies do not confirm the safety and/or scientific validity of the study’s sponsor and/or study investigators. Also, the studies below and linked from this page does not mean the study was evaluated or approved by the U.S. Federal Government.
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