Trulicity (Page 5 of 7)

13 NONCLINICAL TOXICOLOGY

13.1 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 mg/kg (0.2-, 3-, 8-, and 24-fold the MRHD of 4.5 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 ≥3-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 (24 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, and 3 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 [see Boxed Warning and Warnings and Precautions (5.1)].

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 (55-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 (≥13-fold the MRHD based on AUC), which occurred in the presence of decreased maternal food consumption and body weight gain.

13.2 Animal Toxicology and/or Pharmacology

Zucker diabetic fatty (ZDF) rats were given 0.5, 1.5, or 5 mg/kg/twice weekly of dulaglutide (1-, 3-, and 13-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 200-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.

14 CLINICAL STUDIES

14.1 Glycemic Control Trials in Adults with Type 2 Diabetes Mellitus

TRULICITY has been studied 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 study with TRULICITY doses up to 4.5 mg added to metformin. All other clinical studies 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).

Monotherapy

In a double-blind study with primary endpoint at 26 weeks, 807 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 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 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%.

Table 4: Results at Week 26 in a Trial of TRULICITY as Monotherapya

Abbreviation: HbA1c = hemoglobin A1c.

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 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.

b Least-squares 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 265 individuals in each of the treatment arms.

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 7.6 7.6 7.6
Change from baselineb -0.7 -0.8 -0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 164 161
Change from baselineb -26 -29 -24
Body Weight (kg) (Mean)
Baseline 91.8 92.7 92.4
Change from baselineb -1.4 -2.3 -2.2

Combination Therapy

Add-on to Metformin

In this placebo-controlled, double-blind study with primary endpoint at 52 weeks, 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% and 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 weeks), all in combination with metformin (Table 5 and Figure 3).

Table 5: Results at Week 52 of TRULICITY Compared to Sitagliptin used as Add-On to Metformina

Abbreviations: HbA1c = hemoglobin A1c.

a All 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.

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 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%.

52-Week Primary Time Point
TRULICITY0.75 mg TRULICITY1.5 mg Sitagliptin100 mg
Intent-to-Treat (ITT) Population (N) 281 279 273
HbA1c (%) (Mean)
Baseline 8.2 8.1 8.0
Change from baselineb -0.9 -1.1 -0.4
Difference from sitagliptinb (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)
Baseline 174 173 171
Change from baselineb -30 -41 -14
Difference from sitagliptinb (95% CI) -15 (-22, -9) -27 (-33, -20)
Body Weight (kg) (Mean)
Baseline 85.5 86.5 85.8
Change from baselineb -2.7 -3.1 -1.5
Difference from sitagliptinb (95% CI) -1.2 (-1.8, -0.6) -1.5 (-2.1, -0.9)
Figure 3
(click image for full-size original)

Figure 3: Adjusted Mean HbA1c at each Time Point (ITT, MMRM) and at Week 52 (ITT, LOCF)

TRULICITY 3 mg and 4.5 mg Add-on to Metformin

In this parallel-arm, double-blind study with primary endpoint at 36 weeks, a total of 1842 patients were randomized 1:1:1 to TRULICITY 1.5 mg, TRULICITY 3 mg, or TRULICITY 4.5 mg once weekly, all as add-on to metformin (NCT03495102).

Following randomization, all patients received TRULICITY 0.75 mg once weekly. The dose was increased every 4 weeks to the next higher dose until the patients reached the assigned study dose (1.5 mg, 3 mg, or 4.5 mg). Patients were to remain on the assigned study dose for the duration of the study.

Patients had a mean age of 57.1 years; a mean duration of type 2 diabetes of 7.6 years; 51.2% were male; race: White, Black, and Asian were 85.8%, 4.5%, and 2.4%, respectively; and 27.6% of the study population was in the US.

At 36 weeks, treatment with TRULICITY 4.5 mg resulted in a statistically significant reduction in HbA1c and in body weight compared to TRULICITY 1.5 mg (Table 6 and Figure 4).

Table 6. Results at Week 36 of TRULICITY 1.5 mg Compared to 3 mg and 4.5 mg as Add-On to Metformina

Abbreviations: HbA1c = hemoglobin A1c

a Intent-to-treat population. At Week 36, primary efficacy was missing for 7%, 7%, and 6% of individuals treated with TRULICITY 1.5 mg, TRULICITY 3 mg, and TRULICITY 4.5 mg, respectively.

b Least-squares mean adjusted for baseline value and other stratification factors. Missing data were imputed using multiple imputation.

c Patients with missing HbA1c data at Week 36 were considered as not achieving HbA1c target.

^ p=0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.

^^ p<0.0001 for superiority compared to TRULICITY 1.5 mg, overall type I error controlled.

36-Week Primary Time Point
TRULICITY 1.5 mg TRULICITY 3 mg TRULICITY 4.5 mg
Intent-to-Treat (ITT) Population (N) 612 616 614
HbA1c (%) (Mean)
Baseline 8.6 8.6 8.6
Change from baselineb -1.5 -1.6 -1.8
Difference from 1.5 mgb (95% CI) -0.1 (-0.2, 0.0) -0.2 (-0.4, -0.1) ^
Percentage of patients HbA1c <7.0% c 50 56 62
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 185 184 183
Change from baselineb -45 -46 -51
Difference from 1.5 mgb (95% CI) – 2 (-7, 3) -6 (-11, -2)
Body Weight (kg) (Mean)
Baseline 95.5 96.3 95.4
Change from baselineb -3.0 -3.8 -4.6
Difference from 1.5 mgb (95% CI) -0.9 (-1.4, -0.4) -1.6 (-2.2, -1.1) ^^
Figure 4
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Figure 4: Mean HbA1c at each Time Point (ITT) and at Week 36 (ITT, MI)

Add-on to Sulfonylurea

In this 24-week placebo-controlled, double-blind study, 299 patients were randomized to and received placebo or once weekly TRULICITY 1.5 mg, both as add-on to glimepiride. Patients had a mean age of 58 years; mean duration of type 2 diabetes of 8 years; 44% were male; race: White, Black, and Asian were 83%, 4%, and 2%, respectively; and 24% of the study population were in the US.

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 Glimepiridea

Abbreviations: HbA1c = hemoglobin A1c.

a Intent-to-treat population. Data post-onset of rescue therapy are treated as missing. At Week 24 primary efficacy was missing for 10% and 12% of individuals randomized to TRULICITY 1.5 mg and placebo, respectively.

b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to the baseline values, was used to model a wash-out of the treatment effect for subjects having missing Week 24 data.

c Patients with missing HbA1c data at Week 24 were considered as non-responders.

†† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.

24-Week Primary Time Point
Placebo TRULICITY1.5 mg
Intent-to-Treat (ITT) Population (N) 60 239
HbA1c (%) (Mean)
Baseline 8.4 8.4
Change from baselineb -0.3 -1.3
Difference from placebob (95% CI) -1.1 (-1.4, -0.7)††
Percentage of patients HbA1c <7.0% c 17 50††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 175 178
Change from baselineb 2 -28
Difference from placebob (95% CI) -30 (-44, -15)††
Body Weight (kg) (Mean)
Baseline 89.5 84.5
Change from baselineb -0.2 -0.5
Difference from placebob (95% CI) -0.4 (-1.2, 0.5)

Add-on to Metformin and Thiazolidinedione

In this placebo-controlled study with primary endpoint at 26 weeks, 976 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 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 8 and Figure 5). 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 8: Results at Week 26 of TRULICITY Compared to Placebo and Exenatide, All as Add-On to Metformin and Thiazolidinedionea

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

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 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. The primary analysis included 119, 269, 271 and 266 individuals randomized to placebo, TRULICITY 0.75 mg, TRULICITY 1.5 mg, and exenatide, respectively.

‡‡ 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%.

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)
Baseline 8.1 8.1 8.1 8.1
Change from baselineb -0.5 -1.3 -1.5 -1.0
Difference from placebob (95% CI) -0.8 (-1.0, -0.7)‡‡ -1.1 (-1.2, -0.9)‡‡
Difference from exenatideb (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)
Baseline 166 159 162 164
Change from baselineb -5 -34 -42 -24
Difference from placebob (95% CI) -30 (-36, -23) -38 (-45, -31)
Difference from exenatideb (95% CI) -10 (-15, -5) -18 (-24, -13)
Body Weight (kg) (Mean)
Baseline 94.1 95.5 96.2 97.4
Change from baselineb 1.2 0.2 -1.3 -1.1
Difference from placebob (95% CI) -1.0 (-1.8, -0.3) -2.5 (-3.3, -1.8)
Difference from exenatideb (95% CI) 1.3 (0.6, 1.9) -0.2 (-0.9, 0.4)
Figure 5
(click image for full-size original)

Figure 5: Adjusted Mean HbA1c at Each Time Point (ITT, MMRM) and at Week 26 (ITT, LOCF)

Combination Therapy with SGLT2i, with or without Metformin

In this 24-week placebo-controlled, double-blind study, 423 patients were randomized to and received TRULICITY 0.75 mg, TRULICITY 1.5 mg, or placebo, as add-on to sodium-glucose co-transporter 2 inhibitor (SGLT2i) therapy (96% with and 4% without metformin). Trulicity was administered once weekly, and SGLT2i was administered according to the local country label. Patients had a mean age of 57 years; mean duration of type 2 diabetes of 9.4 years; 50% were male; race: White, Black, and Asian were 89%, 3%, and 0.2%, respectively; and 21% of the study population was in the US.

At 24 weeks, treatment with once weekly TRULICITY 0.75 mg and 1.5 mg resulted in a statistically significant reduction from baseline in HbA1c compared to placebo (Table 9).

The mean baseline body weight was 90.5, 91.1, and 92.9 kg in the placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg groups, respectively. The mean changes from baseline in body weight at Week 24 were -2.0, -2.5, and -2.9 kg for placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively. The difference from placebo (95% CI) was -0.9 kg (-1.7, -0.1) for TRULICITY 1.5 mg.

Table 9: Results at Week 24 of TRULICITY as Add-on to SGLT2ia

Abbreviations: HbA1c = hemoglobin A1c; SGLT2i = sodium-glucose co-transporter-2 inhibitors.

a Intent-to-treat population. At Week 24, primary efficacy was missing for 3%, 4%, and 6% of individuals treated with placebo, TRULICITY 0.75 mg, and TRULICITY 1.5 mg, respectively.

b Least-squares mean adjusted for baseline value and other stratification factors. Placebo multiple imputation, using baseline and 24-week values from the placebo arm, was applied to model a washout of the treatment effect for patients missing 24-week values (HbA1c, fasting serum glucose, and body weight).

c Patients with missing HbA1c data at Week 24 were considered as non-responders.

†† p<0.001 for superiority of TRULICITY compared to placebo, overall type I error controlled.

24-Week Primary Time Point
Placebo TRULICITY 0.75 mg TRULICITY 1.5 mg
Intent-to-Treat (ITT) Population (N) 140 141 142
HbA1c (%) (Mean)
Baseline 8.1 8.1 8.0
Change from baselineb -0.6 -1.2 -1.3
Difference from placebob (95% CI) -0.7 (-0.8, -0.5)†† -0.8 (-0.9, -0.6)††
Percentage of patients HbA1c <7.0% c 31 59†† 67††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 153 162 161
Change from baselineb -6 -25 -30
Difference from placebob (95% CI) -19 (-25, -13) -24 (-30, -18)††

Add-on to Metformin and Sulfonylurea

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 52 weeks, 807 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. 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 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 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 10). 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 10: Results at Week 52 of TRULICITY Compared to Insulin Glargine, Both as Add-on to Metformin and Sulfonylureaa

Abbreviations: HbA1c = hemoglobin A1c.

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.

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)
Baseline 8.1 8.2 8.1
Change from baselineb -0.8 -1.1 -0.6
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 161 165 163
Change from baselineb -16 -27 -32
Difference from insulin glargineb (95% CI) 16 (9, 23) 5 (-2, 12)
Body Weight (kg) (Mean)
Baseline 86.4 85.2 87.6
Change from baselineb -1.3 -1.9 1.4
Difference from insulinb (95% CI) -2.8 (-3.4, -2.2) -3.3 (-3.9, -2.7)

Combination Therapy with Basal Insulin, with or without Metformin

In this 28-week placebo-controlled, double-blind study, 300 patients were randomized to placebo or once weekly TRULICITY 1.5 mg, as add-on to titrated basal insulin glargine (with or without metformin). Patients had a mean age of 60 years; mean duration of type 2 diabetes of 13 years; 58% were male; race: White, Black, and Asian were 94%, 4%, and 0.3%, respectively; and 20% of the study population was in the US.

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%.

At 28 weeks, treatment with once weekly TRULICITY 1.5 mg resulted in a statistically significant reduction in HbA1c compared to placebo (Table 11).

Table 11: Results at Week 28 of TRULICITY Compared to Placebo as Add-On to Basal Insulina

Abbreviations: HbA1c = hemoglobin A1c.

a Intent-to-treat population. At Week 28, primary efficacy was missing for 12% and 8% of individuals randomized to placebo and TRULICITY 1.5 mg, respectively.

b Least-squares mean from ANCOVA adjusted for baseline value and other stratification factors. Placebo multiple imputation, with respect to baseline values, was used to model a wash-out of the treatment effect for subjects having missing Week 28 data.

c Patients with missing HbA1c data at Week 28 were considered as non-responders.

†† p<0.001 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.

p≤0.005 for superiority of TRULICITY 1.5 mg compared to placebo, overall type I error controlled.

28-Week Primary Time Point
Placebo TRULICITY1.5 mg
Intent-to-Treat (ITT) Population (N) 150 150
HbA1c (%) (Mean)
Baseline 8.3 8.4
Change from baselineb -0.7 -1.4
Difference from placebob (95% CI) -0.7 (-0.9, -0.5)††
Percentage of patients HbA1c <7.0% c 33 67††
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 156 157
Change from baselineb -30 -44
Difference from placebob (95% CI) -14 (-23, -4)
Body Weight (kg) (Mean)
Baseline 92.6 93.3
Change from baselineb 0.8 -1.3
Difference from placebob (95% CI) -2.1 (-2.9, -1.4)††

Combination Therapy with Prandial Insulin, with or without Metformin

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, 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 12).

Table 12: Results at Week 26 of TRULICITY Compared to Insulin Glargine, Both in Combination with Insulin Lisproa

Abbreviation: HbA1c = hemoglobin A1c

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 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.

26-Week Primary Time Point
TRULICITY0.75 mg TRULICITY1.5 mg Insulin Glargine
Intent-to-Treat (ITT) Population (N) 293 295 296
HbA1c (%) (Mean)
Baseline 8.4 8.5 8.5
Change from baselineb -1.6 -1.6 -1.4
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 150 157 154
Change from baselineb 4 -5 -28
Difference from insulin glargineb (95% CI) 32 (24, 41) 24 (15, 32)
Body Weight (kg) (Mean)
Baseline 91.7 91.0 90.8
Change from baselineb 0.2 -0.9 2.3
Difference from insulin glargineb (95% CI) -2.2 (-2.8, -1.5) -3.2 (-3.8, -2.6)

Moderate to Severe Chronic Kidney Disease

In this open-label comparator study (double-blind with respect to TRULICITY dose assignment) with primary endpoint at 26 weeks, a total of 576 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. At randomization, patients discontinued their pre-study insulin regimen and patients 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. 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 had a mean age of 65 years; a mean duration of type 2 diabetes of 18 years; 52% were male; race: White, Black, and Asian were 69%, 16%, and 3%, respectively; and 32% of the study population were in the US. At baseline, overall mean eGFR was 38 mL/min/1.73 m2 , 30% of patients had eGFR <30 mL/min/1.73 m2 , and 45% of patients had macroalbuminuria. Patients on over 70 units/day of basal insulin were excluded from the study.

Treatment with TRULICITY 0.75 mg and 1.5 mg once weekly resulted in a reduction in HbA1c at 26-weeks 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%. Mean fasting plasma glucose increased in the TRULICITY arms (Table 13).

Mean baseline body weight was 90.9 kg, 88.1 kg, and 88.2 kg in the TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine arms, respectively. The mean changes from baseline at Week 26 were -1.1, -2, and 1.9 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 Diseasea

Abbreviation: HbA1c = hemoglobin A1c

a Intent-to-treat population (all randomized and treated subjects) was used in the analysis regardless of discontinuation of study drug or initiation of rescue therapy. At Week 26, primary efficacy was missing for 12%, 15%, and 9% of individuals randomized to and treated with TRULICITY 0.75 mg, TRULICITY 1.5 mg, and insulin glargine, respectively. Missing data were imputed using multiple imputation within treatment group.

b Least-squares (LS) mean from ANCOVA pattern mixture model adjusted for baseline value and other stratification factors.

26-Week Primary Time Point
TRULICITY0.75 mg TRULICITY1.5 mg Insulin Glargine
Intent-to-Treat Population (N) 190 192 194
HbA1c (%) (Mean)
Baseline 8.6 8.6 8.6
Change from baselineb -0.9 -1.0 -1.0
Difference from insulin glargineb (95% CI) 0.0 (-0.2, 0.3) -0.1 (-0.3, 0.2)
Percentage of patients HbA1c <8.0% 73 75 74
Fasting Serum Glucose (mg/dL) (Mean)
Baseline 167 161 170
Change from baselineb 6 14 -23
Difference from insulin glargineb (95% CI) 30 (16, 43) 37 (24, 50)

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