Trulicity - Pharmaceutical Information, Clinical Trials, Detailed Pharmacology, Toxicology.
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Trulicity - Scientific Information

Manufacture: Eli Lilly and Company
Country: United States
Condition: Diabetes Mellitus, Diabetes, Type 2
Class: Antidiabetic agents, Incretin mimetics
Form: Liquid solution, Subcutaneous (SC)
Ingredients: Dulag lutide, Triso dium Citra te Dihydrate, Anhydrous Citric Acid, Mannitol, Polysorbate 80, Water

Description

TRULICITY contains dulaglutide, a human GLP-1 receptor agonist. The molecule is a fusion protein that consists of 2 identical, disulfide-linked chains, each containing an N-terminal GLP -1 analog sequence covalently linked to the Fc portion of a modified human immunoglobulin G4 (IgG4) heavy chain by a small peptide linker and is produced using mammalian cell culture. The GLP-1 analog portion of dulaglutide is 90% homologous to native human GLP-1 (7-37). Structural modifications were introduced in the GLP-1 part of the molecule responsible for interaction with the enzyme dipeptidyl-peptidase IV (DPP-4). Additional modifications were made in an area with a potential T-cell epitope and in the areas of the IgG4 Fc part of the molecule responsible for binding the high-affinity Fc receptors and half-antibody formation. The overall molecular weight of dulaglutide is approximately 63 kilodaltons.

TRULICITY is a clear, colorless, sterile solution. Each 0.5 mL of TRULICITY solution contains 0.75 mg or 1.5 mg of dulaglutide. Each single-dose pen or prefilled syringe contains 0.5 mL of solution and

the following excipients: citric acid anhydrous (0.07 mg), mannitol (23.2 mg), polysorbate 80 (0.10 mg), trisodium citrate dihydrate (1.37 mg), in water for injection.

Clinical Pharmacology

Mechanism of Action

TRULICITY contains dulaglutide, which is a human GLP -1 receptor agonist with 90% amino acid sequence homology to endogenous human GLP- 1 (7-37). Dulaglutide activates the GLP-1 receptor, a membrane-bound cell- surface receptor coupled to adenylyl cyclase in pancreatic beta cells. Dulaglutide increases intracellular cyclic AMP (cAMP) in beta cells leading to glucose-dependent insulin release. Dulaglutide also decreases glucagon secretion and slows gastric emptying.

Pharmacodynamics

TRULICITY lowers fasting glucose and reduces postprandial glucose (PPG) concentrations in patients with type 2 diabetes mellitus. The reduction in fasting and postprandial glucose can be observed after a single dose.

Fasting and Postprandial Glucose

In a clinical pharmacology study in adults with type 2 diabetes mellitus, treatment with once weekly TRULICITY resulted in a reduction of fasting and 2-hour PPG concentrations, and postprandial serum glucose incremental AUC, when compared to placebo (-25.6 mg/dL,-59.5 mg/dL, and -197 mg h/dL, respectively); these effects were sustained after 6 weeks of dosing with the 1.5 mg dose.

First- and Second-Phase Insulin Secretion

Both first-and second-phase insulin secretion were increased in patients with type 2 diabetes treated with TRULICITY compared with placebo.

Insulin and Glucagon Secretion

TRULICITY stimulates glucose-dependent insulin secretion and reduces glucagon secretion. Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly increased fasting insulin from baseline at Week 26 by 35.38 and 17.50 pmol/L, respectively, and C-peptide concentration by 0.09 and 0.07 nmol/L, respectively, in a Phase 3 monotherapy study. In the same study, fasting glucagon concentration was reduced by 1.71 and 2.05 pmol/L from baseline with TRULICITY 0.75 mg and 1.5 mg, respectively.

Gastric Motility

Dulaglutide causes a delay of gastric emptying. The delay is largest after the first dose and diminishes with subsequent doses.

Cardiac Electrophysiology (QTc)

The effect of dulaglutide on cardiac repolarization was tested in a thorough QTc study. Dulaglutide did not produce QTc prolongation at supratherapeutic doses of 4 and 7 mg.

Pharmacokinetics

The pharmacokinetics of dulaglutide is similar between healthy subjects and patients with type 2 diabetes mellitus. Following subcutaneous administration, the time to maximum plasma concentration of dulaglutide at steady -state ranges from 24 to 72 hours, with a median of 48 hours. After multiple-dose administration of 1.5 mg to steady state, the mean peak plasma concentration (Cmax) and total systemic exposure (AUC) of dulaglutide were 114 ng/mL (range 56 to 231 ng/mL) and 14,000 ng*h/mL (range 6940 to 26,000 ng*h/mL), respectively; accumulation ratio was approximately 1.56. Steady-state plasma dulaglutide concentrations were achieved between 2 and 4 weeks following once weekly administration. Site of subcutaneous administration (abdomen, upper arm, and thigh) had no statistically significant effect on the exposure to dulaglutide.

Absorption – The mean absolute bioavailability of dulaglutide following subcutaneous administration of single 0.75 mg and 1.5 mg doses was 65% and 47%, respectively.

Distribution – The mean volumes of distribution after subcutaneous administration of TRULICITY 0.75 mg and 1.5 mg to steady state were approximately 19.2 L (range 14.3 to 26.4 L) and 17.4 L (range 9.3 to 33 L), respectively.

Metabolism – Dulaglutide is presumed to be degraded into its component amino acids by general protein catabolism pathways.

Elimination – The mean apparent clearance at steady state of dulaglutide is approximately 0.111 L/h for the 0.75 mg dose, and 0.107 L/h for the 1.5 mg dose. The elimination half-life of dulaglutide for both doses is approximately 5 days.

Specific Populations

No dose adjustment of dulaglutide is needed based on age, gender, race, ethnicity, body weight, or renal or hepatic impairment. The effects of intrinsic factors on the PK of dulaglutide are shown in Figure 1.



Figure 1: Impact of intrinsic factors on dulag lutide pharmacokinetics.

Renal – Dulaglutide systemic exposure was increased by 20, 28, 14 and 12% for mild, moderate, severe, and ESRD renal impairment sub-groups, respectively, compared to subjects with normal renal function. The corresponding values for increase in C max were 13, 23, 20 and 11%, respectively (Figure 1).

Hepatic - Dulaglutide systemic exposure decreased by 23, 33 and 21% for mild, moderate and severe hepatic impairment groups, respectively, compared to subjects with normal hepatic function, and Cmax was decreased by a similar magnitude (Figure 1).

Drug Interactions

The potential effect of co -administered medications on the PK of dulaglutide and vice-versa was studied in several single- and multiple-dose studies in healthy subjects, patients with type 2 diabetes mellitus, and patients with hypertension.

Potential for Dulaglutide to Influence the Pharmacokinetics of Other Drugs

Dulaglutide slows gastric emptying and, as a result, may reduce the extent and rate of absorption of orally co-administered medications. In clinical pharmacology studies, dulaglutide did not affect the absorption of the tested orally administered medications to any clinically relevant degree.

Pharmacokinetic (PK) measures indicating the magnitude of these interactions are presented in Figure 2. No dose adjustment is recommended for any of the evaluated co-administered medications.



Figure 2: Impact of dulaglutide on the pharmacokinetics of co-administered medications.

Potential for Co-administered Drugs to Influence the Pharmacokinetics of Dulaglutide

In a clinical pharmacology study, the coadministration of a single dose of dulaglutide (1.5 mg) with steady-state sitagliptin (100 mg) caused an increase in dulaglutide AUC and Cmax of approximately 38% and 27%, which is not considered clinically relevant.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 2-year carcinogenicity study was conducted with dulaglutide in male and female rats at doses of 0.05, 0.5, 1.5, and 5.0 mg/kg (0.5-, 7 -, 20-, and 58-fold the MRHD of 1.5 mg once weekly based on AUC) administered by subcutaneous injection twice weekly. In rats, dulaglutide caused a dose-related and treatment-duration-dependent increase in the incidence of thyroid C-cell tumors (adenomas and/or carcinomas) compared to controls, at ≥7-fold the MRHD based on AUC. A statistically significant increase in C-cell adenomas was observed in rats receiving dulaglutide at ≥0.5 mg/kg). Numerical increases in thyroid C- cell carcinomas occurred at 5 mg/kg (58 times the MRHD based on AUC) and were considered to be treatment-related despite the absence of statistical significance.

A 6-month carcinogenicity study was conducted with dulaglutide in rasH2 transgenic mice at doses of 0.3, 1.0, and 3.0 mg/kg administered by subcutaneous injection twice weekly. Dulaglutide did not produce increased incidences of thyroid C-cell hyperplasia or neoplasia at any dose.

Dulaglutide is a recombinant protein; no genotoxicity studies have been conducted.

Human relevance of thyroid C-cell tumors in rats is unknown and could not be determined by clinical studies or nonclinical studies.

In fertility and early embryonic development studies in male and female rats, no adverse effects of dulaglutide on sperm morphology, mating, fertility, conception, and embryonic survival were observed at up to 16.3 mg/kg (130 -fold the MRHD based on AUC). In female rats, an increase in the number of females with prolonged diestrus and a dose-related decrease in the mean number of corpora lutea, implantation sites, and viable embryos were observed at ≥4.9 mg/kg (≥32-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.

Animal Toxicology and/or Pharmacology

Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5.0 mg/kg/twice weekly of dulaglutide (3-, 8-, and 30-fold the MRHD based on AUC) for 3 months. Increases of 12% to 33% in total and pancreatic amylase, but not lipase, were observed at all doses without microscopic pancreatic inflammatory correlates in individual animals. Other changes in the dulaglutide-treated animals included increased interlobular ductal epithelium without active ductal cell proliferation (≥0.5 mg/kg), increased acinar atrophy with/without inflammation (≥1.5 mg/kg), and increased neutrophilic inflammation of the acinar pancreas (5 mg/kg).

Treatment of monkeys for 12 months with 8.15 mg/kg/twice weekly of dulaglutide (nearly 500-fold the MRHD based on AUC) demonstrated no evidence of pancreatic inflammation or pancreatic intraepithelial neoplasia. In 4 of 19 monkeys on dulaglutide treatment, there was an increase in goblet cells within the pancreatic ducts, but no differences from the control group in total amylase or lipase at study termination. There were no proliferative changes in the thyroid C-cells.

Clinical Studies

TRULICITY has been studied as monotherapy and in combination with metformin, metformin and sulfonylurea, metformin and thiazolidinedione, and prandial insulin with or without metformin.

The studies evaluated the use of TRULICITY 0.75 mg and 1.5 mg. Uptitration was not performed in any of the trials; 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).

Monotherapy

In a 52-week double-blind study (26 week primary endpoint), 807 patients inadequately treated with diet and exercise, or with diet and exercise and one anti-diabetic 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 study 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 the 26 week primary timepoint (Table 1). 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%.

Table 1: Results at Week 26 in a Trial of TRULICITY as Monotherapya
  26-Week Primary Time Point
TRULICITY
0.75 mg
TRULICITY
1.5 mg
Metformin
1500-2000 mg
Intent-to-Treat (ITT) Population (N)‡ 270 269 268
HbA1c (%) (Mean)
Baseline HbA1c 7.6 7.6 7.6
Change from baseline (adjusted mean) -0.7 -0.8 -0.6
Fas ting Serum Glucos e (mg/dL) (Mean)
Baseline 161 164 161
Change from baseline (adjusted mean) -26 -29 -24
Body Weight (kg) (Mean)
Baseline (mean) 91.8 92.7 92.4
Change from baseline (adjusted mean) -1.4 -2.3 -2.2

Abbreviation: HbA1c = hemoglobin A1c.

Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 265 individuals in each of the treatment arms.

aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 10%, 12% and 14 % of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and metformin, respectively.

Combination Therapy

Add-on to Metformin

In this 104-week placebo-controlled, double- blind study (52-week primary endpoint), 972 patients were randomized to placebo, TRULICITY 0.75 mg once weekly, TRULICITY 1.5 mg once weekly, 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. Patients had a mean age of 54 years; mean duration of type 2 diabetes of 7 years; 48% were male; race: White, Black and Asian were 53%, 4% and 27%, respectively; and 24% of the study population were in the US.

At the 26 week placebo-controlled time point, the HbA1c change was 0.1%, -1.0%, -1.2%, and -0.6% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. The percentage of patients who achieved HbA1c <7.0% was 22%, 56%, 62%, 39% for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. At 26 weeks, there was a mean weight reduction of 1.4 kg, 2.7 kg, 3.0 kg, and 1.4 kg for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively. There was a mean reduction of fasting glucose of 9 mg/dL, 35 mg/dL, 41 mg/dL, and 18 mg/dL for placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and sitagliptin, respectively.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to sitagliptin (at 26 and 52), all in combination with metformin (Table 2 and Figure 4)

Table 2: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformina
52-Week Primary Time Point
TRULICITY
0.75 mg
TRULICITY
1.5 mg
Sitagliptin
100 mg
Intent-to-Treat (ITT) Population (N) 281 279 273
HbA1c (%) (Mean)b
Baseline 8.2 8.1 8
Change from baseline (adjusted mean) -0.9 -1.1 -0.4
Difference from sitagliptin (95% CI) -0.5 (-0.7, -0.3)†† -0.7 (-0.9, -0.5)†† -
Percentage of patients HbA1c
<7.0%
49 ## 59## 33
Fasting Plasma Glucose (mg/dL) (Mean)b
Baseline 174 173 171
Change from baseline (adjusted mean) -30 -41 -14
Difference from sitagliptin (95% CI) -15 (-22, -9) -27 (-33, -20) -
Body Weight (kg) (Mean)b
Baseline (mean) 85.5 86.5 85.8
Change from baseline (adjusted mean) -2.7 -3.1 -1.5
Difference from sitagliptin (95% CI) -1.2 (-1.8, -0.6) -1.5 (-2.1, -0.9) -

aAll ITT patients randomized after the dose-finding portion of the study. Last observation carried forward (LOCF) was used to impute missing data. At Week 52 primary efficacy was missing for 15%, 19%, and 20% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively.

bLeast-squares (LS) mean adjusted for baseline value and other stratification factors.

Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 276, 277, and 270 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and sitagliptin, respectively.

††Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to sitagliptin, assessed only for HbA1c.

##p<0.001 TRULICITY compared to sitagliptin, assessed only for HbA1c <7.0%.



Add-on to Metformin and Thiazolidinedione

In this 52 -week placebo-controlled study (26 -week primary endpoint), 976 patients were randomized to 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 study blind. 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. Patients had a mean age of 56 years; mean duration of type 2 diabetes of 9 years; 58% were male; race: White, Black and Asian were 74%, 8% and 3%, respectively; and 81% of the study population were in the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a statistically significant reduction in HbA1c compared to placebo (at 26 weeks) and compared to exenatide at 26 weeks (Table 5 and Figure 4). Over the 52-week study 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.

Table 3: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin and Thiazolidinedionea
  26-Week Primary Time Point
Placebo TRULICITY
0.75 mg
TRULICITY
1.5 mg
Exenatide
10 mcg BID
Intent-to-Treat (ITT)
Population (N)
141 280 279 276
HbA1c (%) (Mean)b
Baseline 8.1 8.1 8.1 8.1
Change from baseline
(adjusted mean)
-0.5 -1.3 -1.5 -1.0
Difference from placebo
(95% CI)
- -0.8 (-1.0, -0.7)‡‡ -1.1 (-1.2, -0.9)‡‡ -
Difference from exenatide
(95% CI)
- -0.3 (-0.4, -0.2)†† -0.5 (-0.7, -0.4)†† -
Percentage of patients
HbA1c <7.0%
43 66**, ## 78**, ## 52
Fasting Serum Glucose (mg/dL) (Mean)b
Baseline 166 159 162 164
Change from baseline
(adjusted mean)
-5 -34 -42 -24
Difference from placebo
(95% CI)
- -30 (-36, -23) -38 (-45, -31) -
Difference from exenatide
(95% CI)
- -10 (-15, -5) -18 (-24, -13) -
Body Weight (kg) (Mean)b
Baseline (mean) 94.1 95.5 96.2 97.4
Change from baseline
(adjusted mean)
1.2 0.2 -1.3 -1.1
Difference from placebo
(95% CI)
- -1.0 (-1.8, -0.3) -2.5 (-3.3, -1.8) -
Difference from exenatide
(95% CI)
- 1.3 (0.6, 1.9) -0.2 (-0.9, 0.4) -

Abbreviations: BID = twice daily; HbA1c = hemoglobin A1c.

aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 23%, 10%, 7% and 12% of individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.

b Least-squares (LS) mean adjusted for baseline value and other stratification factors.

Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment.

‡‡ Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to placebo, assessed only for HbA1c.

†† Multiplicity adjusted 1-sided p-value <0.001, for superiority of TRULICITY compared to exenatide, assessed only for HbA1c.

** p<0.001 TRULICITY compared to placebo, assessed only for HbA1c <7.0%. ## p<0.001 TRULICITY compared to exenatide, assessed only for HbA1c <7.0%.



Figure 4: Adjusted Mean HbA1c Chang e at Each Time Point (ITT) and at Week 26 (ITT) - LOCF

Add-on to Metformin and Sulfonylurea

In this 78-week (52 -week primary endpoint) open-label comparator study (double-blind with respect to TRULICITY dose assignment), 807 patients were randomized to 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. This was followed by a 6- to 8-week glycemic stabilization period prior to randomization.

Patients randomized to insulin glargine were started on a dose of 10 U 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 study 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. 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 glargine.

Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9 years; 51% were male; race: White, Black and Asian were 71%, 1% and 17%, respectively; and 0% of the study population were in the US.

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 6). The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.

Table 4: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylureaa
  52-Week Primary Time Point
TRULICITY
0.75 mg
TRULICITY
1.5 mg
Insulin Glargine
Intent-to-Treat (ITT) Population
(N)
272 273 262
HbA1c (%) (Mean)b
Baseline 8.1 8.2 8.1
Change from baseline (adjusted
mean)
-0.8 -1.1 -0.6
Fasting Serum Glucose (mg/dL) (Mean)b
Baseline 161 165 163
Change from baseline (adjusted
mean)
-16 -27 -32
Difference from insulin glargine.
Adjusted mean (95% CI)
16 (9,23) 5 (-2, 12) -
Body Weight (kg) (Mean)b
Baseline (mean) 86.4 85.2 87.6
Change from baseline (adjusted
mean)
-1.3 -1.9 1.4
Difference from insulin. Adjusted
mean (95% CI)
-2,8 (-3,4 -2,2) -3,3 (-3,9 - 2,7) -

a Intent- to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 52, primary efficacy was missing for 17%, 13% and 12% of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively.

b Least-squares (LS) mean adjusted for baseline value and other stratification factors.

‡‡Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 267, 263 and 259 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.

Add-on to Prandial Insulin, with or without Metformin

In this 52-week (26 -week primary endpoint) open-label comparator study (double-blind with respect to TRULICITY dose assignment), 884 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-study 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-study 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.

Patients had a mean age of 59 years; mean duration of type 2 diabetes of 13 years; 54% were male; race: White, Black and Asian were 79%, 10% and 4%, respectively; and 33% of the study population were in the US.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c from baseline. The difference in observed effect size between TRULICITY 0.75 mg and 1.5 mg, respectively, and glargine in this trial excluded the pre-specified non-inferiority margin of 0.4%.

Table 5: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lisproa
  26-Week Primary Time Point
TRULICITY
0.75 mg
TRULICITY
1.5 mg
Insulin Glargine
Intent-to-Treat (ITT) Population (N) 293 295 296
HbA1c (%) (Mean)b
Baseline 8.4 8.5 8.5
Change from baseline (adjusted
mean)
-1.6 -1.6 -1.4
Fasting Serum Glucose (mg/dL)
(Mean)b
Baseline 150 157 154
Change from baseline (adjusted
mean)
4 -5 -28
Difference from insulin glargine.
Adjusted mean (95% CI)
32 (24, 41) 24 (15, 32) -
Body Weight (kg) (Mean)b
Baseline (mean) 91.7 91 90.8
Change from baseline (adjusted
mean)
0.2 -0.9 2.3
Difference from insulin glargine.
Adjusted mean (95% CI)
-2,2 (-2,8, -1,5) -3.2 (-3.8, -2.6) -

aIntent-to-treat population. Last observation carried forward (LOCF) was used to impute missing data. Data post-onset of rescue therapy are treated as missing. At Week 26, primary efficacy was missing for 14 %, 15%, and 14 % of individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg and glargine, respectively.

b Least-squares (LS) mean adjusted for baseline value and other stratification factors.

Subjects included in the analysis are a subset of the ITT population that had at least one post-baseline assessment. The primary analysis included 275, 273 and 276 individuals randomized to TRULICITY 0.75 mg, TRULICITY 1.5 mg, and glargine, respectively.