Summary Basis of Decision for Trulicity

Clinical Pharmacology

Trulicity contains the medicinal ingredient dulaglutide, which is a long‑acting glucagon‑like peptide 1 (GLP‑1) receptor agonist. Like endogenous GLP‑1, Trulicity helps regulate postprandial blood glucose concentrations by increasing intracellular cyclic adenosine monophosphate (cAMP) in pancreatic beta cells leading to insulin release in the presence of elevated glucose concentrations. This insulin secretion subsides as blood glucose concentrations decrease and approach euglycemia. Trulicity also decreases glucagon secretion and slows gastric emptying, thereby reducing the rate at which postprandial glucose appears in the circulation.

For further details, please refer to the Trulicity Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The Clinical program included more than 35 clinical studies, however only the data relevant to the indications and the conditions of use of this product shall be summarized below.

The efficacy of Trulicity was evaluated primarily in four controlled Phase III clinical studies, H9X‑MC‑GBCF, H9X‑MC‑GBDE, H9X‑MC‑GBDB, and H9X‑MC‑GBDD. The primary efficacy endpoint for all four studies was the change in glycated hemoglobin (HbA1c) from baseline. The timing of the primary endpoint assessment ranged from 26 weeks to 52 weeks, depending on the study.

Trulicity was also evaluated in Study H9X‑MC‑GBCM in patients with renal impairment for whom metformin is inappropriate due to contraindication or intolerance

Clinical Studies

Study H9X‑MC‑GBCF: Add-On Combination Therapy to Metformin

Study H9X‑MC‑GBCF was a 104-week, multicentre, double‑blind, placebo‑controlled study. A total of 972 patients with type 2 diabetes mellitus (T2DM) were randomized and received either Trulicity 0.75 mg or Trulicity 1.5 mg administered once‑weekly, placebo, or sitagliptin 100 mg/day (after 26 weeks, patients in the placebo treatment group received blinded sitagliptin 100 mg/day for the remainder of the study), all as add-on to metformin. Randomization occurred after an 11-week lead-in period to allow for a metformin titration period followed by a 6-week glycemic stabilization period. The primary objective of the study was to demonstrate that the HbA1c change from baseline for Trulicity 1.5 mg administered once‑weekly was non‑inferior to sitagliptin at 52 weeks, with a non‑inferiority margin of 0.25%.

Study results showed that treatment with Trulicity once‑weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 52 weeks). The proportions of patients who achieved a HbA1c target of <7% were 49%, 59% and 33% in the Trulicity 0.75 mg, Trulicity 1.5 mg, and sitagliptin groups respectively.

Study H9X‑MC‑GBDE: Add‑On Combination Therapy to Metformin

Study H9X‑MC‑GBDE was a 26‑week, multicentre, open-label study where 599 patients were randomized to receive either once‑weekly Trulicity 1.5 mg or once daily liraglutide 1.8 mg, both as add‑on to metformin. Patients randomized to liraglutide were initiated at 0.6 mg daily (QD) for one week, then escalated to 1.2 mg QD for one week and then escalated to 1.8 mg QD for the remainder of the study. The primary objective of this study was to demonstrate the non‑inferiority of Trulicity 1.5 mg administered once‑weekly compared to liraglutide 1.8 mg QD, both on a background of metformin, in achieving HbA1c reduction from baseline when compared to Week 26, with a non‑inferiority margin of 0.4%.

Study results obtained at Week 26 demonstrated that treatment with Trulicity 1.5 mg once‑weekly was non‑inferior to liraglutide 1.8 mg QD; with both on a background to metformin. The percentage of patients achieving an HbA1c target of <7% was 68% in the Trulicity 1.5 mg group versus (vs) 68% in the liraglutide group.

Study H9X‑MC‑GBDB: Add‑On Combination Therapy to Metformin and Sulfonylurea

Study H9X‑MC‑GBDB was a 78‑week multicentre, parallel‑arm, open-label (double‑blind with respect to Trulicity dose assignment), active comparator (insulin glargine) study. A total of 807 patients were randomized and received either Trulicity 0.75 mg or Trulicity 1.5 mg administered once‑weekly compared to insulin glargine QD, 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. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.

At randomization, patients assigned to the insulin glargine arm were started on a dose of 10 units QD. Insulin glargine dose adjustments occurred twice‑weekly for the first 4 weeks of treatment based on self-measured fasting plasma glucose, followed by once‑weekly titration through Week 8 of study treatment, utilizing an algorithm with an fasting plasma glucose (FPG) target of <5.6 mmol/L. After Week 8, patients continued to self-adjust insulin glargine to the FPG target. The insulin glargine dose was also reviewed and revised, as needed, at subsequent office visits (Weeks 14, 20, 26, 35, 44, 52, 65, and 78). The dose of glimepiride could be reduced or discontinued after randomization (at the discretion of the investigator) in the event of persistent hypoglycemia.

The primary objective of the study was to demonstrate the non‑inferiority of Trulicity 1.5 mg once‑weekly compared to insulin glargine (titrated to target FPG of <5.6 mmol/L), both on a background of metformin and glimepiride, in achieving HbA1c reduction from baseline compared to Week 52, with a non‑inferiority margin of 0.4%. Only 23.5% of patients in the insulin glargine group achieved the target FPG. The dose of glimepiride was reduced or discontinued in 28%, 32%, and 29% of patients randomized to Trulicity 0.75 mg, Trulicity 1.5 mg, and insulin glargine.

Study results at the 52‑week time point demonstrated that Trulicity 1.5 mg and 0.75 mg were non‑inferior to insulin glargine for HbA1c change from baseline. The proportion of patients who achieved an HbA1c target of <7% were 37%, 53% and 31% in the Trulicity 0.75 mg, Trulicity 1.5 mg and insulin glargine groups respectively.

Study H9X‑MC‑GBDD: Combination Therapy with Insulin Lispro (with or without Metformin)

Study H9X‑MC‑GBDD was a 52‑week Phase III, randomized, parallel‑arm, open-label (double‑blind with respect to Trulicity dose assignment) active comparator (insulin glargine) study. This study evaluated the efficacy of either Trulicity 0.75 mg or Trulicity 1.5 mg administered once‑weekly, both in combination with insulin lispro, with or without metformin, in patients with T2DM previously treated with a stable, conventional insulin regimen for at least three months.

A total of 884 patients on one or two insulin injections QD, alone or with oral antihyperglycemic therapy, were enrolled. Randomization occurred after a 9‑week lead‑in period. During the initial two weeks of the lead‑in period, patients continued their pre‑study insulin regimen, but could also be initiated and/or up-titrated with metformin, based at investigator discretion. This was then followed by a 7‑week glycemic stabilization period prior to randomization.

At randomization, patients discontinued their pre‑study insulin regimen and were randomized to Trulicity 0.75 mg or 1.5 mg administered once‑weekly, or insulin glargine QD, all in combination with prandial insulin lispro three times daily, with or without metformin. Insulin lispro was titrated in both arms based on pre‑prandial and bedtime glucose, and insulin glargine was titrated based on a target fasting glucose of <5.6 mmol/L.

The primary objective of the study was to demonstrate non‑inferiority of Trulicity 1.5 mg once‑weekly compared to insulin glargine, both in combination with prandial insulin lispro, in HbA1c reduction from baseline at 26 weeks, with a non‑inferiority margin of 0.4%. Only 35.8% of patients in the glargine arm achieved their target fasting glucose.

Study results at the 26‑week time point demonstrated that Trulicity 1.5 mg was non‑inferior to insulin glargine for HbA1c change from baseline. Trulicity 0.75 mg was also non‑inferior to insulin glargine. The proportion of patients who achieved a HbA1c target of <7% were 69%, 68% and 57% in the Trulicity 0.75 mg, Trulicity 1.5 mg, and insulin glargine groups respectively.

Study H9X-MC-GBCM: Renal Impairment 

Study H9X-MC-GBCM was a parallel‑design, open‑label, multicentre, single‑dose study in patients with renal impairment and control subjects with normal renal function. A total of 48 subjects were enrolled and completed this study: eight patients in each of the renally impaired groups (mild, moderate, severe, and end‑stage renal disease) and 16 healthy (control) subjects. There was no clinically relevant effect of renal impairment on the pharmacokinetics of Trulicity.  A single subcutaneous dose of 1.5 mg Trulicity was generally well‑tolerated in all renal function groups. There were no trends of clinical concern with respect to safety and increase in renal impairment. This data indicated that Trulicity may be administered to patients with renal impairment without dose adjustment.

Other Supporting Data Addressing Renal Impairment 

In placebo-controlled studies with a duration of ≥26 weeks, the majority of patients did not change their chronic kidney disease (CKD) stage (all doses of Trulicity: 91.7%; placebo: 90.1%). Numerically fewer patients in the Trulicity treatment arms had CKD stage that became worse compared to placebo (6.6% and 8.4%, respectively). Moreover, no Trulicity dose‑effects were observed with serum creatinine level or the estimated glomerular filtration rate (eGFR). Significant, decreases were observed for albumin excretion in Trulicity 1.5 mg treatment arm compared with Trulicity 0.75 mg.

A total of 425 (7.1%) patients in Phase II and III studies had a degree of renal impairment at baseline [eGFR <60 mL/min/1.73 m² and/or macroalbuminuria (urine albumin creatinine ratio) (UACR) >300 mg/g)]. A total of 270 (6.7%) of Trulicity-treated patients had renal impairment.  In patients with renal dysfunction at baseline, treatment with Trulicity did not alter serum creatinine or eGFR compared to placebo.

Indication

In the New drug Submission (NDS) the sponsor had proposed the following indication: Trulicity is indicated for the once-weekly treatment of patients with type 2 diabetes mellitus to improve glycemic control, in combination with:

• diet and exercise in patients for whom metformin is inappropriate due to contraindication or intolerance.
• metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
• metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
• metformin and a thiazolidinedione when diet and exercise plus dual therapy with metformin and thiazolidinedione do not achieve adequate glycemic control.
• prandial insulin (with or without metformin) when diet and exercise plus prandial insulin (with or without metformin) do not achieve adequate glycemic control.

The approved indication by Health Canada is as follows:

Trulicity is indicated for the once-weekly treatment of adult patients with type 2 diabetes mellitus to improve glycemic control, in combination with:

• diet and exercise in patients for whom metformin is inappropriate due to contraindication or intolerance.
• metformin, when diet and exercise plus maximal tolerated dose of metformin do not achieve adequate glycemic control.
• metformin and a sulfonylurea, when diet and exercise plus dual therapy with metformin and a sulfonylurea do not achieve adequate glycemic control.
• prandial insulin with metformin, when diet and exercise plus basal or basal-bolus insulin therapy (up to two injections of basal or basal plus prandial insulin per day) with or without oral antihyperglycemic medications, do not achieve adequate glycemic control.

Note, the combination therapy with thiazolidinediones was not granted due to the cardiovascular risk inherent with this class of products. Also, the combination with prandial insulin was revised to reflect the research study design, along with current clinical practice in Canada.

Clinical Safety

The safety of Trulicity in patients with type 2 diabetes mellitus (T2DM) was evaluated across nine Phase II and III clinical studies, including a total of 4,006 patients (for 3,531 patient-years) who received Trulicity. A total of 3,045 patients received Trulicity for at least 24 weeks, with 2,279 patients continuing treatment for at least 50 weeks. A total of 369 patients were treated with Trulicity for approximately two years.

In placebo‑controlled studies of at least 26‑week duration, the incidence of discontinuation due to adverse events was 2.6% for Trulicity 0.75 mg and 6.1% for Trulicity 1.5 mg versus 3.7% for placebo. Through the full duration of the studies (up to 104 weeks), the incidence of discontinuation due to adverse events was 5.1% and 8.4% for Trulicity 0.75 mg and 1.5 mg respectively. The most frequent adverse events leading to discontinuation for 0.75 mg and 1.5 mg Trulicity were nausea (1.0%, 1.9%), diarrhea (0.5%, 0.6%), and vomiting (0.4%, 0.6%).

The proportion of patients reporting at least one treatment‑emergent adverse event (TEAE) was 68.1% for Trulicity 0.75 mg, 71.6% for Trulicity 1.5 mg, and 66.7% with placebo. Gastrointestinal adverse events appeared to be dose‑dependent with more Trulicity 1.5 mg treated patients (21.1%) than Trulicity 0.75 mg treated patients (12.4%) reporting these events compared to placebo (5.3%). The most frequently reported gastrointestinal events were nausea (12.4% for 0.75 mg, 21.1% for 1.5 mg vs 5.3% for placebo), diarrhea (8.9%, 12.6% vs 6.7%), and vomiting (6.0%, 12.6% vs 2.3%). In studies up to 104 weeks, gastrointestinal events continued to be the most common TEAEs reported.

In placebo‑controlled studies of 26‑weeks duration, the incidence of serious adverse events (SAEs) was 3.9% for patients treated with Trulicity 0.75 mg, 4.4% for patients treated with Trulicity 1.5 mg, and 4.4% for patients treated with placebo.

Adverse Events of Special Interest

Pancreatitis 

A total of 151 patients had events/criteria that underwent pancreatic adjudication in Phase II and III studies. Of these, 19 patients had TEAEs of pancreatitis reported by investigators. Of the 151 patients (including the 19 who reported TEAE pancreatitis), nine patients [placebo: 1 (3.523/1,000 patient-year); sitagliptin: 3 (4.707/1,000 patient‑year); dulaglutide: 5 (1.416/1,000 patient-year)] were determined to have pancreatitis by adjudication. Six of these patients were considered to have acute pancreatitis, two had chronic pancreatitis, and one had type unknown.

Immunogenicity

The incidence of treatment-emergent Trulicity anti-drug antibodies in Trulicity‑treated patients were low, 1.6% (64 of 3,907); for patients treated with non‑GLP‑1 receptor agonist comparators (controls), it was 0.7%. These generally represented low titer findings with only four Trulicity-treated patients having high titers (≥1:128). Of the 64 (1.6%) Trulicity‑treated patients with treatment‑emergent anti-drug antibodies, 34 (0.9% of total population) had Trulicity neutralizing anti-drug antibodies, and four patients (0.1% of the total population) had native sequence GLP‑1 neutralizing antibodies. There was no evidence that treatment‑emergent Trulicity anti-drug antibodies interfere with the pharmacological effects of Trulicity on efficacy parameters. No Trulicity‑treated patient with treatment‑emergent Trulicity anti-drug antibodies reported a systemic hypersensitivity reaction.

Thyroid

Trulicity did not increase mean serum calcitonin values compared with placebo. Similar proportions of patients who received placebo or Trulicity had treatment‑emergent calcitonin ≥20 pg/mL. There was no apparent dose‑effect on calcitonin. One case of medullary thyroid carcinoma (MTC), identified after six months of treatment with dulaglutide 2 mg but considered to be pre‑existing, was reported during Phase II and III studies. Two papillary thyroid carcinomas were also identified, both in patients who received Trulicity 1.5 mg.

Cardiovascular

Dose‑dependent increases from baseline in mean heart rate (HR) [2 to 4 beats per minute (bpm)] were observed with Trulicity treatment. The increases were greater for Trulicity compared with placebo. These increases were also greater for Trulicity 1.5 mg than with 0.75 mg. The increases in HR were not associated with increased reporting of tachyarrhythmias by electrocardiogram (ECG) rhythm assessments or adverse events reporting. Increases in mean PR interval (2 to 3 milliseconds) were observed along with increased reporting of 1st degree atrioventricular block.

Malignancy

There was no increased reporting of malignancy in general or any specific malignancy type with Trulicity compared with placebo or active comparators. Two cases of pancreatic carcinoma were identified in Trulicity‑treated patients: one event was determined to be pre‑existing and the other was a large tumour discovered after approximately 5 months of Trulicity treatment.

Dose-Dependent Safety (Trulicity 0.75 mg vs Trulicity 1.5 mg)

The overall safety profile for Trulicity 0.75 mg and Trulicity 1.5 mg was comparable for the majority of safety measures. A dose-dependent increase in heart rate (range: 2 to 4.6 bpm) was observed with Trulicity treatment versus placebo in a Phase II study. The mean increases were greater for the Trulicity 1.5 mg dose compared with the Trulicity 0.75 mg dose from Week 4 through Week 26. The 1.5 mg dose was also associated with a higher risk of gastrointestinal disorders and discontinuation rate at the beginning of treatment (first 2 weeks). Dose-dependent increases in gastrointestinal adverse events were most notably nausea (12% for 0.75 to 21% for 1.5 mg) and vomiting (6% for 0.75 and 13% for 1.5 mg). Overall discontinuation rate was low due to gastrointestinal disorders but was higher in the 1.5 mg dose group (3.5%) compared with the 0.75 mg dose group (1.3%). A dose‑dependent increase in pancreatic enzymes was also observed, however, the clinical relevance is unknown.

Other Safety Issues

Injection Site Reactions

In the placebo‑controlled clinical studies, injection site adverse events were reported in 38 (1.7%) Trulicity‑treated patients compared to 6 (0.9%) patients in the placebo group. Injection site hematoma was the most frequently reported injection site reaction for both the placebo (3, 0.4%) and all Trulicity (17, 0.8%) treatment groups. Injection site pain (6, 0.3%) and erythema (4, 0.2%) were only reported in the Trulcity treatment group. Two Trulicity-treated patients discontinued study drug due to injection site reaction.

In studies of up to 104 weeks 1.9% of patients in the Trulicity 0.75 mg and 1.5 mg groups reported injection site reactions. Again injection site hematoma was the most commonly reported event (Trulicity 0.75 mg: 15, 0.9% and Trulicity 1.5 mg: 10, 0.6%). One patient in this group discontinued study drug due to injection site reaction.

Across the clinical studies of 26 up to 104 weeks duration, potentially immune‑mediated injection site adverse events [for example (e.g.), rash, and erythema] were reported in 0.5% and 0.7% of patients who received Trulicity 0.75 mg and 1.5 mg, respectively.

Hypoglycemia

When Trulicity was used in combination with a non-sulfonylurea, non-secretagogue, documented symptomatic hypoglycemia occurred in 2.6% to 6.3% of patients treated with Trulicity 0.75 mg and in 5.6% to 10.9% of patients treated with Trulicity 1.5 mg. No episodes of severe hypoglycemia were reported.

When Trulicity was used in combination with a sulfonylurea (plus metformin), symptomatic hypoglycemia occurred in 39% of patients treated with Trulicity 0.75 mg and 40.3% of patients treated with Trulicity 1.5 mg. Severe hypoglycemia events occurred in 0% of patients treated with Trulicity 0.75 mg and 0.7% of patients treated with Trulicity 1.5 mg.

When Trulicity was used in combination with prandial insulin, symptomatic hypoglycemia occurred in 85.3% of patients treated with Trulicity 0.75 mg and 80.0% of patients treated with Trulicity1.5 mg. Severe hypoglycemia events occurred in 2.4% and 3.4% of patients respectively for Trulicity 0.75 mg and 1.5 mg.

Hypersensitivity

In clinical studies, systemic hypersensitivity events (e.g. severe urticaria, systemic rash, facial edema, lips swelling) were reported in 0.5% of patients receiving Trulicity.

Safety Conclusion

For more information, refer to the Trulicity Product Monograph, approved by Health Canada and available through the Drug Product Database.