Trulicity Drug Information

Overview of Clinical Trials Trulicity has been studied in adults as monotherapy and in combination with metformin, sulfonylurea, metformin and sulfonylurea, metformin and thiazolidinedione, sodium-glucose co-transporter-2 inhibitors (SGLT2i) with or without metformin, basal insulin with or without metformin, and prandial insulin with or without metformin. Trulicity has also been studied in patients with type 2 diabetes mellitus and moderate to severe renal impairment. Dose escalation was performed in one trial in adults with Trulicity doses up to 4.5 mg added to metformin.

All other clinical studies in adults evaluated Trulicity 0.75 mg and 1.5 mg without dose escalation; patients were initiated and maintained on either 0.75 mg or 1.5 mg for the duration of the trials. In patients with type 2 diabetes mellitus, Trulicity produced reductions from baseline in HbA1c compared to placebo. No overall differences in glycemic effectiveness were observed across demographic subgroups (age, gender, race/ethnicity, duration of diabetes).

A cardiovascular outcomes trial was conducted in adult patients with type 2 diabetes mellitus and established cardiovascular (CV) disease or multiple cardiovascular risk factors. Patients were randomized to Trulicity 1.5 mg or placebo both added to standard of care. Trulicity significantly reduced the risk of first occurrence of primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke.

Glycemic Control Monotherapy Trials in Adults with Type 2 Diabetes Mellitus In a double-blind trial with primary endpoint at 26 weeks, 807 adult patients inadequately treated with diet and exercise, or with diet and exercise and one antidiabetic agent used at submaximal dose, were randomized to Trulicity 0.75 mg once weekly, Trulicity 1.5 mg once weekly, or metformin 1500 to 2000 mg/day following a two-week washout. Seventy-five percent (75%) of the randomized population were treated with one antidiabetic agent at the screening visit. Most patients previously treated with an antidiabetic agent were receiving metformin (~90%) at a median dose of 1000 mg daily and approximately 10% were receiving a sulfonylurea.

Patients had a mean age of 56 years and a mean duration of type 2 diabetes of 3 years. Forty-four percent were male. The White, Black and Asian race accounted for 74%, 7% and 8% of the population, respectively.

Twenty-nine percent of the trial population were from the US. Treatment with Trulicity 0.75 mg and 1.5 mg once weekly resulted in reduction in HbA1c from baseline at 26-weeks ( Table 4 ). The difference in observed effect size between Trulicity 0.75 mg and 1.5 mg, respectively, and metformin excluded the pre-specified non-inferiority margin of 0.4%.

Randomization occurred after an 11-week lead-in period to allow for a metformin titration period, followed by a 6-week glycemic stabilization period. At the 26-week placebo-controlled time point, the HbA1c change was for placebo, Trulicity 0.75 mg, Trulicity 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c for placebo, Trulicity 0.75 mg, Trulicity 1.5 mg, and sitagliptin, respectively.

Following randomization, all patients received Trulicity 0.75 mg once weekly. Patients were to remain on the assigned study dose for the duration of the trial. Table 6.

At 24 weeks, treatment with once weekly Trulicity 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo ( Table 7 ). Table 7: Results at Week 24 of Trulicity Compared to Placebo as Add-On to Glimepiride in Adult Patients with Type 2 Diabetes Mellitus a -Controlled Trial (Add-on to Metformin and Thiazolidinedione) In this placebo-controlled trial with primary endpoint at 26 weeks, 976 adult patients were randomized to and received placebo, Trulicity 0.75 mg once weekly, Trulicity 1.5 mg once weekly, or exenatide 10 mcg BID, all as add-on to maximally tolerated doses of metformin (≥1500 mg per day) and pioglitazone (up to 45 mg per day). Exenatide treatment group assignment was open-label while the treatment assignments to placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg were blinded.

After 26 weeks, patients in the placebo treatment group were randomized to either Trulicity 0.75 mg once weekly or Trulicity 1.5 mg once weekly to maintain blinding. Randomization occurred after a 12-week lead-in period; during the initial 4 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and pioglitazone; this was followed by an 8-week glycemic stabilization period prior to randomization. Patients randomized to exenatide started at a dose of 5 mcg BID for 4 weeks and then were escalated to 10 mcg BID.

Over the 52-week trial period, the percentage of patients who required glycemic rescue was 8.9% in the Trulicity 0.75 mg once weekly + metformin and pioglitazone treatment group, 3.2% in the Trulicity 1.5 mg once weekly + metformin and pioglitazone treatment group, and 8.7% in the exenatide BID + metformin and pioglitazone treatment group. Trulicity was administered once weekly, and SGLT2i was administered according to the local country label. The mean changes from baseline in body weight at Week kg for placebo, Trulicity 0.75 mg, and Trulicity 1.5 mg, respectively.

Table 9: Results at Week 24 of Trulicity as Add-on to SGLT2i in Adult Patients with Type 2 Diabetes Mellitus a Controlled Trial (Add-on to Metformin and Sulfonylurea) In this open-label comparator trial (double-blind with respect to Trulicity dose assignment) with primary endpoint at 52 weeks, 807 adult patients were randomized to and received Trulicity 0.75 mg once weekly, Trulicity 1.5 mg once weekly, or insulin glargine once daily, all as add-on to maximally tolerated doses of metformin and glimepiride. Randomization occurred after a 10-week lead-in period; during the initial 2 weeks of the lead-in period, patients were titrated to maximally tolerated doses of metformin and glimepiride. Patients randomized to insulin glargine were started on a dose of 10 units once daily.

Insulin glargine dose adjustments occurred twice weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose (FPG), followed by once weekly titration through Week 8 of treatment, utilizing an algorithm that targeted a fasting plasma glucose of <100 mg/dL. Only 24% of patients were titrated to goal at the 52-week primary endpoint. The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia.

Treatment with Trulicity once weekly resulted in a reduction in HbA1c from baseline at 52 weeks when used in combination with metformin and sulfonylurea ( Table 10 ). Table 10: Results at Week 52 of Trulicity Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylurea in Adult Patients with Type 2 Diabetes Mellitus a -Controlled Trial (Add-on to Basal Insulin, with or without Metformin) In this 28-week placebo-controlled, double-blind trial, 300 adult patients were randomized to placebo or once weekly Trulicity 1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). The mean starting dose of insulin glargine was 37 units/day for patients receiving placebo and 41 units/day for patients receiving Trulicity 1.5 mg.

At randomization, the initial insulin glargine dose in patients with HbA1c <8.0% was reduced by 20%. Table 11: Results at Week 28 of Trulicity Compared to Placebo as Add-On to Basal Insulin in Adult Patients with Type 2 Diabetes Mellitus a -Controlled Trial (Combination with Prandial Insulin, with or without Metformin) In this open-label comparator trial (double-blind with respect to Trulicity dose assignment) with primary endpoint at 26 weeks, 884 adult patients on 1 or 2 insulin injections per day were enrolled. Randomization occurred after a 9-week lead-in period; during the initial 2 weeks of the lead-in period, patients continued their pre-trial insulin regimen but could be initiated and/or up-titrated on metformin, based on investigator discretion; this was followed by a 7-week glycemic stabilization period prior to randomization.

At randomization, patients discontinued their pre-trial insulin regimen and were randomized to Trulicity 0.75 mg once weekly, Trulicity 1.5 mg once weekly, or insulin glargine once daily, all in combination with prandial insulin lispro 3 times daily, with or without metformin. Insulin lispro was titrated in each arm based on preprandial and bedtime glucose, and insulin glargine was titrated to a fasting plasma glucose goal of <100 mg/dL. Only 36% of patients randomized to glargine were titrated to the fasting glucose goal at the 26-week primary timepoint.

Table 12: Results at Week 26 of Trulicity Compared to Insulin Glargine, Both in Combination with Insulin Lispro in Adult Patients with Type 2 Diabetes Mellitus a.4 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus and Moderate to Severe Chronic Kidney Disease In this open-label comparator trial (double-blind with respect to Trulicity dose assignment) with primary endpoint at 26 weeks, a total of 576 adult patients with type 2 diabetes were randomized and treated to compare Trulicity 0.75 mg and 1.5 mg with insulin glargine (NCT01621178). Patients on insulin and other antidiabetic therapy (e.g., oral antidiabetic drugs, pramlintide) had non-insulin therapies discontinued and had their insulin dose adjusted for 12 weeks prior to randomization. Patients on insulin therapy alone maintained a stable insulin dose for 3 weeks prior to randomization.

For patients randomized to insulin glargine, the initial insulin glargine dose was based on the basal insulin dose prior to randomization. Insulin glargine was allowed to be titrated with a fasting plasma glucose goal of ≤150 mg/dL. Insulin lispro was allowed to be titrated with a preprandial and bedtime glucose goal of ≤180 mg/dL.

Patients on over 70 units/day of basal insulin were excluded from the trial. Mean fasting plasma glucose increased in the Trulicity arms ( Table 13 ). The mean changes from baseline at Week kg in the Trulicity 0.75 mg, Trulicity 1.5 mg, and insulin glargine arms, respectively.

Table 13: Results at Week 26 of Trulicity Compared to Insulin Glargine, Both in Combination with Insulin Lispro, in Patients with Moderate to Severe Chronic Kidney Disease in Adult Patients with Type 2 Diabetes Mellitus a.5 Cardiovascular Outcomes Trial in Adults with Type 2 Diabetes Mellitus and Cardiovascular Disease or Multiple Cardiovascular Risk Factors The REWIND trial (NCT01394952) was a multi-national, multi-center, randomized, placebo-controlled, double-blind trial. The median follow-up duration was 5.4 years. The primary endpoint was the time to the first occurrence of a composite 3-component Major Adverse Cardiovascular Events (MACE) outcome, which included CV death, non-fatal myocardial infarction (MI), and non-fatal stroke.

Patients eligible to enter the trial were 50 years of age or older who had type 2 diabetes mellitus, had an HbA1c value ≤9.5% with no lower limit at screening, and had either established CV disease, or did not have established CV disease but had multiple CV risk factors. Patients who were confirmed to have established CV disease (31.5% of randomized patients) had a history of at least one of the following: MI (16.2%); myocardial ischemia by a stress test or with cardiac imaging (9.3%); ischemic stroke (5.3%); coronary, carotid, or peripheral artery revascularization (18.0%); unstable angina (5.9%); or hospitalization for unstable angina with at least one of the following: ECG changes, myocardial ischemia on imaging, or a need for percutaneous coronary intervention (12.0%). Patients confirmed to be without established CV disease, but with multiple CV risk factors, comprised 62.8% of the randomized trial population.

At baseline, demographic and disease characteristics were balanced between treatment groups. The median baseline HbA1c was 7.2%. At baseline, 94.7% of patients were taking antidiabetic medication, with 10.5% of patients taking three or more antidiabetic drugs.

The most common background antidiabetic drugs used at baseline were metformin (81.2%), sulfonylurea (46.0%), and insulin (23.9%). During the trial, investigators were to modify anti-diabetic and cardiovascular medications to achieve local standard of care treatment targets with respect to blood glucose, lipids, and blood pressure, and manage patients recovering from an acute coronary syndrome or stroke event per local treatment guidelines. For the primary analysis, a Cox proportional hazards model was used to test for superiority.

Type I error was controlled across multiple tests. Vital status was available for 99.7% of patients in the trial. A total of 1128 deaths were recorded during the REWIND trial.

A majority of the deaths in the trial were adjudicated as CV deaths, and non-CV deaths were comparable between the treatment groups (4.4% in patients treated with Trulicity and 5.0% in patients treated with placebo). Figure 6. KAPLAN MEIER CURVE: Time to First Occurrence of MACE in the REWIND Trial Table 14: Treatment Effect for MACE and the Individual Components in the REWIND Trial, Median Trial Observation Time of 5.4 years in Adult Patients with Type 2 Diabetes Mellitus a.6 Glycemic Control Trial in Pediatric Patients 10 Years of Age and Older with Type 2 Diabetes Mellitus In this 26-week randomized, double-blind, placebo-controlled, parallel-arm, multicenter trial with an open-label extension for an additional 26 weeks,154 pediatric patients 10 years of age and older with type 2 diabetes mellitus, who had inadequate glycemic control despite diet and exercise, were randomized to subcutaneous Trulicity once weekly (0.75 mg and 1.5 mg) or subcutaneous placebo once weekly in combination with or without metformin and/or basal insulin treatment (NCT02963766).

Overall, in this trial demographic and baseline disease characteristics were comparable across the treatment groups. Additionally, 55% were Hispanic or Latino, 42% were not Hispanic or Latino, and 3% had unknown ethnicity. In this trial, once weekly Trulicity (0.75 mg and 1.5 mg, pooled) (with or without metformin and/or basal insulin) was superior to placebo (p<0.001) in the change from baseline at Week 26 in HbA1c in pediatric patients 10 years of age and older with type 2 diabetes mellitus (see Table 15 ).