TECOS, MSD’s Cardiovascular Safety Trial of JANUVIA (sitagliptin), Met Primary Endpoint in Patients with Type 2 Diabetes

MSD, known as Merck (NYSE: MRK) in the United States and Canada, today announced the primary results of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), a placebo-controlled study of the cardiovascular (CV) safety of MSD’s DPP-4 inhibitor, JANUVIA^® (sitagliptin), added to usual care in more than 14,000 patients. The study achieved its primary composite CV endpoint of non-inferiority (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for unstable angina) compared to usual care without sitagliptin. Overall, the primary endpoint occurred in 11.4 percent (n=839) of sitagliptin-treated patients compared with 11.6 percent (n=851) of placebo-treated patients in the Intention-to-Treat (ITT) analysis (HR=0.98; 95% CI [0.89-1.08]), and in 9.6 percent (n=695) of patients in both the sitagliptin and placebo groups in the Per Protocol (PP) analysis (HR=0.98; 95% CI [0.88-1.09]; p<0.001 for non-inferiority). In addition, there was no increase in hospitalization for heart failure, and rates of all-cause mortality were similar in both treatment groups, which were two key secondary endpoints. These data were presented today at the 75^th Scientific Sessions of the American Diabetes Association and were also published in the New England Journal of Medicine.

About JANUVIA ^®

JANUVIA^® is indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus as monotherapy when metformin is inappropriate due to contraindications or intolerance or in combination with metformin, a sulfonylurea, or a PPARγ agonist, or as an add-on to sulfonylurea + metformin or PPARγ agonist + metformin when the current regimen, with diet and exercise does not provide adequate glycemic control. JANUVIA is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dose of insulin do not provide adequate glycemic control.

Important Selected Safety Information About Sitagliptin

JANUVIA is contraindicated in patients who are hypersensitive to any components of this product. JANUVIA should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis.

“Patients with type 2 diabetes need antihyperglycemic medicines to help control their blood sugar. Because these patients are at increased risk for cardiovascular complications, understanding the cardiovascular safety of these medicines is important,” said study co-chair Rury Holman, professor of diabetic medicine and diabetes trials unit director, University of Oxford. “The results from TECOS showed that sitagliptin did not increase the risk of cardiovascular events in a diverse group of patients with type 2 diabetes at high cardiovascular risk.”

Additional Findings from the TECOS CV Safety Trial

TECOS was an event-driven study designed to assess the long-term CV safety of the addition of sitagliptin to usual care, compared to usual care without sitagliptin, in patients with type 2 diabetes and established CV disease. In addition to showing no increased risk for the primary composite CV endpoint, sitagliptin also met the secondary composite CV endpoint (defined as the time to the first confirmed event of any of the following: CV-related death, nonfatal MI, or nonfatal stroke), showing non-inferiority compared to usual care without sitagliptin (HR=0.99; 95% CI [0.89-1.11]; p<0.001 for non-inferiority).

In additional secondary endpoints assessing time to first confirmed event, hospitalization for heart failure was reported in 3.1 percent (n=228) of sitagliptin-treated patients and 3.1 percent (n=229) of placebo-treated patients (HR=1.00; 95% CI [0.83-1.20]). All-cause mortality was similar in both treatment groups, occurring in 7.5 percent (n=547) of patients in the sitagliptin group and 7.3 percent (n=537) in the placebo group (HR=1.01; 95% CI [0.90-1.14]).

Acute pancreatitis was uncommon, occurring in 0.3 percent of patients in the sitagliptin group (n=23) and 0.2 percent of patients in the placebo group (n=12); the difference was not statistically different between groups (p=0.065). Pancreatic cancer was also uncommon, occurring in 0.1 percent of patients in the sitagliptin group (n=9) and 0.2 percent of patients in the placebo group (n=14), and was not statistically different between groups (p=0.322).

In additional secondary analyses of the composite of time to first hospitalization for heart failure or CV death, the first confirmed hospitalization for heart failure or CV death occurred in 7.3 percent (n=538) in the sitagliptin group compared with 7.2 percent (n=525) for placebo (HR=1.02; 95% CI [0.90-1.15]). The proportion of patients with CV death was 5.2 percent (n=380) in the sitagliptin group compared with 5.0 percent (n=366) in the placebo group (HR 1.03; 95% CI [0.89-1.19]).

The proportion of patients with non-CV death was 2.3 percent in both treatment groups. Death due to infection was 0.6 percent and 0.7 percent in the sitagliptin and placebo groups, respectively. A slight reduction in eGFR (estimated glomerular filtration rate), a measure of renal function, was observed in both treatment groups during the study: at month 48, mean change from baseline in eGFR was -4.0 ± 18.4 mL/min/1.73m² in the sitagliptin group compared to -2.8 ± 18.3 mL/min/1.73m² for placebo.

“We believe the results of TECOS provide important clinical information about the cardiovascular safety profile of sitagliptin,” said Dr. Roger M. Perlmutter, president, Merck Research Laboratories. “The TECOS CV safety trial reflects the best efforts of clinical scientists at the University of Oxford, the Duke Clinical Research Institute and MSD on behalf of patients around the world who suffer from type 2 diabetes.”

To minimize any potential effect that differences in glucose control might have on CV outcomes, the study aimed to achieve similar glucose control (glycemic equipoise) between treatment groups. At four months, mean HbA1c level was 0.4 percent lower in the sitagliptin group compared with placebo, and this narrowed to 0.1 percent lower during patient follow-up. This resulted in an overall difference of -0.29 percent in patients treated with sitagliptin versus placebo. Compared with patients treated with placebo, fewer patients treated with sitagliptin received additional antihyperglycemic agents during the study period (1,591 vs. 2,046 patients, respectively; p<0.001) and were less likely to start chronic insulin therapy (542 vs. 744 patients, respectively; p<0.001).

Study Methods and Design

TECOS was led by an independent academic research collaboration between the University of Oxford Diabetes Trials Unit (DTU) and the Duke University Clinical Research Institute (DCRI), and was sponsored by MSD. A total of 14,735 patients from 38 countries were randomized between December 2008 and July 2012. Of these, 14,671 were included in the ITT analysis population, with 7,332 assigned to sitagliptin and 7,339 to placebo, in addition to existing therapy. The median patient follow-up was three years, with a maximum follow-up of 5.7 years.

Patients enrolled in the trial had type 2 diabetes with established CV disease in the coronary, cerebral, or peripheral arteries. Patients were at least 50 years of age, had a baseline HbA1c between 6.5 and 8.0 percent, and were dose-stable for at least three months on either: monotherapy or dual combination therapy with metformin, pioglitazone or a sulfonylurea; or insulin as monotherapy or in combination with a stable dose of metformin. Participants were randomly assigned to treatment with sitagliptin 100 mg daily (50 mg daily if baseline eGFR was ≥30 and <50 mL/min/1.73m²) or matching placebo.

The primary non-inferiority hypothesis was assessed by determining whether the upper bound of the 95 percent confidence interval for the hazard ratio for the risk of the primary composite CV endpoint (time to first event) between the sitagliptin and placebo groups in the PP population did not exceed 1.3, with a key supporting analysis in the ITT population. If non-inferiority on the primary composite CV endpoint was met, superiority was to be evaluated in the ITT population.

Important Selected Safety Information About Sitagliptin (continued)

There have been postmarketing reports of acute pancreatitis, including fatal and non-fatal hemorrhagic or necrotizing pancreatitis, in patients taking JANUVIA. Because these reports are made voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Patients should be informed of the characteristic symptom of acute pancreatitis: persistent, severe abdominal pain. Resolution of pancreatitis has been observed after discontinuation of JANUVIA. If pancreatitis is suspected, JANUVIA and other potentially suspect medicinal products should be discontinued. A dosage adjustment is recommended in patients with moderate or severe renal insufficiency or with end-stage renal disease requiring hemodialysis or peritoneal dialysis.

As with other antihyperglycemic agents, when JANUVIA was used in combination with a sulfonylurea or with insulin, medications known to cause hypoglycemia, the incidence of sulfonylurea- or insulin-induced hypoglycemia was increased over that of placebo. To reduce the risk of sulfonylurea- or insulin-induced hypoglycemia, a lower dose of sulfonylurea or insulin may be considered.

There have been postmarketing reports of serious hypersensitivity reactions in patients treated with JANUVIA including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Onset of these reactions occurred within the first 3 months after initiation of treatment with JANUVIA, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue JANUVIA, assess for other potential causes for the event, and institute alternative treatment for diabetes.

In clinical studies as monotherapy and in combination with other agents, the adverse experiences reported regardless of causality assessment in ≥5% of patients and more commonly than placebo or the active comparator included hypoglycemia, nasopharyngitis, upper respiratory tract infection, headache, and peripheral edema.

For additional adverse experience information, see the product circular.

In clinical studies, the safety and effectiveness of JANUVIA in the elderly (≥65 years) were comparable to those seen in patients <65 years. No dosage adjustment is required based on age. In elderly patients with significant renal insufficiency dosage adjustment may be required.

Before initiating therapy, please consult the full prescribing information.

About MSD

Today's MSD is a global healthcare leader working to help the world be well. MSD is a tradename of Merck & Co., Inc., with headquarters in Kenilworth, N.J., U.S.A. Through our prescription medicines, vaccines, biologic therapies and animal health products, we work with customers and operate in more than 140 countries to deliver innovative health solutions. We also demonstrate our commitment to increasing access to healthcare through far-reaching policies, programs and partnerships.

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