Fasting and postprandial plasma glucose contributions to hemoglobin A1c and time in range in people with diabetes on multiple daily injection insulin therapy: Results from the PRONTO-T1D and PRONTO-T2D clinical trials.

AIMS: To investigate contributions of changes in fasting plasma glucose (FPG) and postprandial glucose (PPG) to changes in hemoglobin A1c (HbA1c) and time-in-range (TIR, 70-180 mg/dL) in people with type 1 diabetes (T1D) and type 2 diabetes (T2D) treated with multiple daily injections (MDI) of insulin lispro (rapid/ultra-rapid formulations). METHODS: Multivariate regression models were used to quantify the contributions of FPG and PPG reductions to change in HbA1c and TIR using data from the PRONTO-T1D (N = 1222) and PRONTO-T2D (N = 673) clinical trials. TIR was derived from 10-point self-monitored blood glucose (SMBG) profiles overall, as well as from continuous glucose monitoring (CGM) in the PRONTO-T1D CGM substudy (n = 269/1222). RESULTS: A 1 mmol/L FPG reduction corresponded with a 0.09-0.12 % (95 % confidence interval [CI] 0.06-0.15 %) HbA1c reduction in PRONTO-T1D and 0.17-0.26 % (95 % CI 0.13-0.30 %) in PRONTO-T2D (both p < 0.0001). A 1 mmol/L PPG reduction corresponded with a 0.05-0.09 % (95 % CI 0.01-0.12 %) HbA1c reduction in PRONTO-T1D (p < 0.001) and 0.10-0.15 % (95 % CI 0.05-0.19 %) in PRONTO-T2D (p < 0.0001). Reductions in FPG and PPG were significantly associated with increased TIR whether derived from SMBG (7.87-12.95 % [95 % CI 6.81-14.23 %]; all p < 0.0001) or CGM (3.35-4.18 % [95 % CI 2.11-5.39 %]; all p < 0.05). CONCLUSIONS: FPG and PPG significantly impact HbA1c and TIR. Balanced management of both FPG and PPG is important to achieve glycemic goals for people with diabetes on MDI insulin therapy. CLINICAL TRIALS REGISTRATION: PRONTO-T1D ClinicalTrials.gov identifier: NCT03214367; PRONTO-T2D ClinicalTrials.gov Identifier: NCT03214380.

Ultra rapid lispro (Lyumjev®) shortens time to recovery from hyperglycaemia compared to Humalog® in individuals with type 1 diabetes on continuous subcutaneous insulin infusion.

AIMS: To compare the time to hyperglycaemia recovery after ultra rapid lispro (URLi; Lyumjev®) versus Humalog in a randomized, double-blind crossover study. MATERIALS AND METHODS: Thirty-two adults with type 1 diabetes on continuous subcutaneous insulin infusion participated in two periods: each period included hyperglycaemia induced by a missed mealtime bolus (day 1) and by suspension of basal insulin delivery (day 2). When hyperglycaemia [plasma glucose (PG) >240 mg/dl] occurred, a correction bolus of URLi or Humalog was given and time to hyperglycaemia recovery (PG = 140 mg/dl), pharmacokinetics and glucodynamics were compared. RESULTS: Following a missed mealtime bolus, URLi significantly reduced maximum PG (-13 mg/dl; p = .02), and produced numerically more rapid decline in PG (23 mg/dl/h; p = .07), and faster recovery from hyperglycaemia (-23 min; p = .1) versus Humalog, although differences were not significant. Following basal suspension, URLi significantly reduced maximum PG (-6 mg/dl; p = .02), and produced faster PG decline (24 mg/dl/h; p < .001) and faster recovery from hyperglycaemia (-16 min; p < .01) vs. Humalog. Following a correction bolus of URLi, accelerated insulin lispro absorption was observed versus Humalog: early 50% tmax was reduced by 6 or 12 min, and AUC0-15min was increased 2.5- or 4.3-fold after correction boluses by subcutaneous infusion (day 1) or injection (day 2), respectively (all p < .001). CONCLUSIONS: During episodes of hyperglycaemia commonly experienced in people with type 1 diabetes, URLi provided a faster recovery versus Humalog from a missed mealtime bolus or during basal insulin suspension. URLi shows significant acceleration of insulin absorption versus Humalog when boluses are administered by subcutaneous infusion or injection.

Efficacy and safety of ultra-rapid lispro versus lispro in children and adolescents with type 1 diabetes: The PRONTO-Peds trial.

AIMS: To evaluate the efficacy and safety of ultra-rapid lispro (URLi) versus lispro in a paediatric population with type 1 diabetes (T1D) in a Phase 3, treat-to-target study. MATERIALS AND METHODS: After a 4-week lead-in to optimize basal insulin, participants were randomized to double-blind URLi (n = 280) or lispro (n = 298) injected 0 to 2 minutes prior to meals (mealtime), or open-label URLi (n = 138) injected up to 20 minutes after start of meals (postmeal). Participants remained on pre-study basal insulin (degludec, detemir or glargine). The primary endpoint was glycated haemoglobin (HbA1c) change from baseline after 26 weeks (noninferiority margin 4.4 mmol/mol [0.4%]). RESULTS: Both mealtime and postmeal URLi demonstrated noninferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi -0.23 mmol/mol (95% confidence interval [CI] -1.84, 1.39) and postmeal URLi -0.17 mmol/mol (95% CI -2.15, 1.81). Mealtime URLi reduced 1-hour postprandial glucose (PPG) daily mean (P = 0.001) and premeal to 1 hour postmeal PPG excursion daily mean (P < 0.001) versus lispro. The rate and incidence of severe, nocturnal or documented hypoglycaemia (<3.0 mmol/L [54 mg/dL]) were similar for all treatments. With mealtime URLi versus lispro, the rate of postdose hypoglycaemia (<3.0 mmol/L) was higher at ≤2 hours (P = 0.034). The incidence of treatment-emergent adverse events was similar for all treatments. More participants reported an injection site reaction with mealtime URLi (7.9%) versus postmeal URLi (2.9%) and lispro (2.7%). CONCLUSIONS: In children and adolescents with T1D, URLi demonstrated good glycaemic control, and noninferiority to lispro in HbA1c change for mealtime and postmeal URLi. When dosed at the beginning of meals, URLi reduced 1-hour PPG and PPG excursions versus lispro.

Evaluation of the Pharmacokinetic Profile of Ultra Rapid Lispro Administered Subcutaneously at Different Injection Sites.

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic profile and glucodynamic response of URLi when administered subcutaneously into the abdomen, upper arm, or thigh. An intravenous (IV) bolus administration was included to determine the absolute bioavailability at each injection site. METHODS: In this Phase I, randomized, open-label, 4-period, crossover study, healthy subjects received a single dose of 15 U URLi subcutaneously into the abdomen, upper arm, or thigh, or by intravenous injection. Serum insulin lispro concentrations and glucodynamic response during a 10-hour euglycemic clamp procedure were assessed after URLi administration. FINDINGS: Total insulin lispro exposure was similar for the abdomen, upper arm, and thigh, and absolute bioavailability was ∼65% at each subcutaneous (SC) injection site. Total and peak insulin action were similar across these SC injection sites. The onset of appearance was <1 minute, and the time to early half-maximal drug concentration occurred at ∼10 minutes across these three SC injection sites. Onset of insulin action occurred at ∼22 minutes, and the early insulin action (for the first hour) was also similar across these SC injection sites. URLi was well tolerated after single SC injections and IV bolus administration. IMPLICATIONS: The pharmacokinetic and glucodynamic profiles of URLi were similar after a single SC dose into the abdomen, upper arm, or thigh. The rate of insulin lispro absorption and early insulin action were maintained regardless of the SC injection site. The current study supports SC injection of URLi into the abdomen, upper arm, and thigh. CLINICALTRIALS: gov identifier: NCT03232983.

Ultra-rapid lispro shows faster pharmacokinetics and reduces postprandial glucose excursions versus Humalog® in patients with type 2 diabetes mellitus in a randomized, controlled crossover meal test early phase study.

AIMS: To compare the pharmacokinetics (PK), glucodynamics (GD) and tolerability following single and multiple daily subcutaneous doses of ultra rapid lispro (URLi) and Humalog® in patients with type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: This was a two-part, randomized, double-blind Phase 1b study. Part A used a six-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 minutes before, immediately before, or 15 minutes after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2 weeks when insulins were administered immediately before the start of the meal. RESULTS: URLi increased the insulin exposure within the first 30 minutes postdose by 2.2-fold and reduced the time to the early half-maximal drug concentration by 22.6% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal. In comparing the same meal-to-dose timing between the insulins, the postprandial glucose excursion over 5 hours was significantly reduced by 29%-105% for all three dose timings (-15, 0 and +15 minutes) with URLi. The PK and GD were sustained after daily subcutaneous dosing for 2 weeks in patients with T2D. URLi had more hypoglycaemic events during the MMTTs; few events occurred for both treatments during the 2 weeks of outpatient dosing. CONCLUSIONS: URLi demonstrated accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared with Humalog and was well tolerated in patients with T2D.

Ultra rapid lispro (URLi) shows accelerated pharmacokinetics and greater reduction in postprandial glucose versus Humalog® in patients with type 1 diabetes mellitus in a randomized, double-blind meal test early-phase study.

AIM: To compare the pharmacokinetics (PK), glucodynamics (GD), and tolerability following single and multiple daily subcutaneous (SC) doses of ultra rapid lispro (URLi) and Humalog® in patients with type 1 diabetes mellitus (T1D). MATERIALS AND METHODS: This was a two-part, randomized, double-blind, Phase 1b study. Part A used a six-period crossover design to assess PK and GD response to a solid mixed meal tolerance test (MMTT) following a single dose of URLi or Humalog administered 15 min before, immediately before, and 15 min after the start of the meal. Part B evaluated URLi or Humalog during 2 weeks of multiple daily dosing with a parallel design. The PK and GD were assessed following MMTTs at the beginning and end of the 2-week period when insulins were administered immediately before the start of the meal. RESULTS: URLi increased the insulin exposure within the first 30 min postdose by 2.2-fold and reduced the time to early half-maximal drug concentration by 37% compared with Humalog. Overall, URLi resulted in better postprandial glucose lowering when dosed before, immediately before, or after a meal compared with Humalog. Comparing the same meal-to-dose timing between the insulins, postprandial glucose excursion over 5 hours was reduced by 40%-44% for all three dose timings (-15, 0, and +15 min) with URLi, achieving statistical significance for the 0- and +15-min timings. The PK and GD profiles were sustained after daily SC dosing for 2 weeks in patients with T1D. The number of documented hypoglycaemic events was similar between URLi and Humalog during the postprandial period of the MMTTs and the outpatient period. CONCLUSIONS: URLi showed accelerated insulin lispro absorption and greater postprandial glucose reduction at different meal-to-dose timings compared with Humalog and was well tolerated in patients with T1D.

Ultra Rapid Lispro (URLi) Accelerates Insulin Lispro Absorption and Insulin Action vs Humalog® Consistently Across Study Populations: A Pooled Analysis of Pharmacokinetic and Glucodynamic Data.

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This pooled analysis compared the pharmacokinetics and glucodynamics between URLi and Humalog® in healthy subjects and patients with type 1 or type 2 diabetes mellitus. METHODS: The analysis included four randomized, double-blind, crossover, single-dose studies (healthy subjects [n = 74], patients with type 1 diabetes [n = 78], and type 2 diabetes [n = 38]) evaluating subcutaneous doses of 7, 15, or 30 U of URLi and Humalog during an 8- to 10-h euglycemic clamp procedure. RESULTS: The pooled analysis showed an ~ 5-min faster onset of appearance, an ~8-fold greater exposure in the first 15 min, a 43% reduction in exposure beyond 3 h, and a 68-min shorter exposure duration with URLi vs Humalog across all study populations and dose range. Compared with Humalog, URLi had a 10-min faster onset of action, a 3-fold greater insulin action in the first 30 min, a 35% reduction in insulin action beyond 4 h, and a 44-min shorter duration of action across all populations and dose range. Overall exposure and insulin action were similar between URLi and Humalog for each dose level and study population. CONCLUSIONS: Across the studied populations and dose range, URLi consistently demonstrated a faster absorption, reduced late exposure, and overall shorter exposure duration compared with Humalog. Similarly, URLi demonstrated earlier insulin action while reducing late insulin action and shorter insulin action compared with Humalog across the study populations and dose range. CLINICAL TRIAL REGISTRATION: NCT02942654 (registered: 21 October, 2016), NCT03286751 (registered: 15 September, 2017), NCT03166124 (registered: 23 May, 2017), and NCT03305822 (registered: 5 October, 2017).

Long-Term Efficacy and Safety of Ultra Rapid Lispro (URLi) in Adults with Type 1 Diabetes: The PRONTO-T1D Extension.

INTRODUCTION: The PRONTO-T1D study, which evaluated the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes (T1D), met the primary endpoint of noninferiority of HbA1c change from baseline compared to lispro at 26 weeks. We present results of an additional 26-week treatment phase evaluating long-term efficacy and safety of URLi. METHODS: In this phase 3, treat-to-target study, subjects were randomized to double-blind mealtime URLi, lispro, or open-label postmeal URLi with insulin degludec or glargine for 26 weeks. Subjects in the double-blind URLi (n = 451) and lispro (n = 442) groups continued for another 26 weeks to assess long-term efficacy and safety. RESULTS: HbA1c increased marginally during the long-term maintenance period (week 26-52) in both groups to 7.47% (URLi) and 7.54% (lispro). At week 52, there were no statistically significant treatment differences in change from baseline HbA1c with a least-squares mean treatment difference (95% confidence interval) of - 0.06% (- 0.16, 0.03). Proportions of patients with HbA1c < 7% at week 52 were similar (URLi, 26.8%; lispro, 24.5%). Self-monitored blood glucose (SMBG) showed that 1-h (9.23 versus 10.14 mmol/L) and 2-h (8.40 versus 9.53 mmol/L) postmeal daily mean glucose was statistically significantly (p < 0.001) lower with URLi than lispro. The rate and incidence of severe, documented, and postprandial hypoglycemia (< 54 mg/dl [3.0 mmol/L]) were similar between treatments, but URLi demonstrated a 31% lower rate in the period more than 4 h after meals, (p = 0.023). Injection site reactions were reported by 3.3% of patients on URLi and 0.9% on lispro. The incidence of treatment-emergent adverse events was similar between treatments. CONCLUSION: Overall glycemic control and improved postprandial glucose via SMBG were maintained after 52 weeks with URLi versus lispro, suggesting that the efficacy of URLi is preserved during long-term treatment in patients with T1D. No long-term safety issues were identified with URLi. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03214367.

Pharmacokinetic and Glucodynamic Responses of Ultra Rapid Lispro vs Lispro Across a Clinically Relevant Range of Subcutaneous Doses in Healthy Subjects.

PURPOSE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetic and glucodynamic parameters of URLi and Lispro (Humalog®) at 3 dose levels in healthy subjects. METHODS: This randomized, 6-period, subject- and investigator-blind, crossover study included 42 healthy subjects. At each period, subjects received a single subcutaneous dose of 7, 15, or 30 U of URLi or Lispro followed by a 10-h automated euglycemic clamp. Insulin lispro and blood glucose concentrations were measured. FINDINGS: Across all 3 doses, insulin lispro appeared in the serum 2-5 min faster, and exposure was 6- to 8-fold greater in the first 15 min, with URLi versus Lispro. Exposure beyond 3 h postdose was 45%-52% lower, and duration of exposure was 67-86 min shorter with URLi versus Lispro for all dose levels. Onset of insulin action was 7-9 min faster and insulin action was ~3-fold greater in the first 30 min with URLi versus Lispro across the dose levels. Insulin action beyond 4 h was reduced by 32%-45%, and duration of action was reduced by 47-67 min, with URLi versus Lispro for all 3 dose levels. Overall exposure and total glucose infused were similar between URLi and Lispro at each dose level. Dose proportionality was observed for maximum and overall exposure after URLi. Less than dose-proportional increases in maximum and total glucose infused were observed and were similar for both URLi and Lispro. IMPLICATIONS: URLi exhibited ultra-rapid pharmacokinetic and glucodynamic parameters across all 3 dose levels studied and exhibited dose-proportional increases in exposure in healthy subjects. ClinicalTrials.gov identifier: NCT03286751.

Bioequivalence of Ultra Rapid Lispro (URLi) U100 and U200 Formulations in Healthy Subjects.

INTRODUCTION: Ultra rapid lispro (URLi) is a novel insulin lispro formulation that was developed to more closely match physiological insulin secretion. The aims of this study were to demonstrate the bioequivalence (BE) of a concentrated formulation (U200) of URLi to the U100 formulation of URLi after subcutaneous (SC) administration and to evaluate the glucodynamics (GD) of these formulations. METHODS: This phase 1, randomized, two-sequence, four-period, double-blind, replicate crossover study was conducted in 68 healthy subjects. At each dosing visit, subjects received a 15-U SC dose of either U100 URLi or U200 URLi followed by a 10-h euglycemic clamp procedure. Serum insulin lispro and blood glucose concentrations were measured, and the glucose infusion rate was continuously adjusted during the clamp to maintain the target blood glucose. RESULTS: Bioequivalence of U200 URLi relative to U100 URLi was demonstrated. The 90% confidence intervals (CIs) of the ratios of geometric least squares (LS) means for the maximum insulin concentration and total exposure were within the BE limits of 0.80-1.25. Additionally, the 90% CIs for the ratios of geometric LS means for maximum glucose infusion rate and total glucose infused were within the BE limits. The early 50% tmax occurred at approximately the same time for the U100 and U200 URLi formulations, and the insulin exposure within the first 15 min was similar for both formulations. The tolerability of the two URLi formulations was comparable. CONCLUSIONS: This study demonstrated that the U100 and U200 URLi formulations are bioequivalent. The accelerated insulin absorption observed for the U100 formulation was maintained with the U200 URLi formulation. Further, the GD were similar for both formulations, supporting the ability of individuals to transfer from U100 to U200 URLi in a 1:1 unit conversion. TRIAL REGISTRATION: NCT03616977.

Ultra rapid lispro improves postprandial glucose control compared with lispro in patients with type 1 diabetes: Results from the 26-week PRONTO-T1D study.

AIMS: To evaluate the efficacy and safety of ultra rapid lispro (URLi) versus lispro in adults with type 1 diabetes in a 26-week, treat-to-target, phase 3 trial. MATERIALS AND METHODS: After an 8-week lead-in to optimize basal insulin glargine or degludec, patients were randomized to double-blind mealtime URLi (n = 451) or lispro (n = 442), or open-label post-meal URLi (n = 329). The primary endpoint was change from baseline glycated haemoglobin (HbA1c) to 26 weeks (non-inferiority margin 0.4%), with multiplicity-adjusted objectives for postprandial glucose (PPG) excursions after a meal test. RESULTS: Both mealtime and post-meal URLi demonstrated non-inferiority to lispro for HbA1c: estimated treatment difference (ETD) for mealtime URLi -0.08% [95% confidence interval (CI) -0.16, 0.00] and for post-meal URLi +0.13% (95% CI 0.04, 0.22), with a significantly higher endpoint HbA1c for post-meal URLi versus lispro (P = 0.003). Mealtime URLi was superior to lispro in reducing 1- and 2-hour PPG excursions during the meal test: ETD -1.55 mmol/L (95% CI -1.96, -1.14) at 1 hour and - 1.73 mmol/L (95% CI -2.28, -1.18) at 2 hours (both P < 0.001). The rate and incidence of severe, documented and postprandial hypoglycaemia (<3.0 mmol/L) was similar between treatments, but mealtime URLi demonstrated a 37% lower rate in the period >4 hours after meals (P = 0.013). Injection site reactions were reported by 2.9% of patients on mealtime URLi, 2.4% on post-meal URLi, and 0.2% on lispro. Overall, the incidence of treatment-emergent adverse events was similar between treatments. CONCLUSIONS: The results showed that URLi provided good glycaemic control, with non-inferiority to lispro confirmed for both mealtime and post-meal URLi, while superior PPG control was demonstrated with mealtime dosing.

Ultra rapid lispro lowers postprandial glucose and more closely matches normal physiological glucose response compared to other rapid insulin analogues: A phase 1 randomized, crossover study.

AIMS: To compare the pharmacokinetic (PK) and glucodynamic (GD) characteristics of ultra rapid lispro (URLi; Eli Lilly and Company, Indianapolis, Indiana), Fiasp® (Novo Nordisk, Bagsvaerd, Denmark), Humalog® (Eli Lilly and Company) and NovoRapid® (Novo Nordisk), in patients with type 1 diabetes (T1D). MATERIALS AND METHODS: This was a randomized, double-blind, four-period, crossover study, conducted in 68 patients with T1D. Patients received the same individualized subcutaneous dose of each study drug immediately prior to a liquid test meal. For comparison, 12 healthy subjects received the same test meal. RESULTS: URLi had a significantly faster insulin absorption compared to the other insulins tested. Early half-maximal drug concentration was reached 13 minutes after administration of URLi, which was 6 minutes faster than Fiasp, 13 minutes faster than Humalog, and 14 minutes faster than NovoRapid (all P <0.0001). Early insulin exposure was significantly greater and late insulin exposure was reduced after URLi compared to the other insulins. URLi achieved the greatest numerical reduction in postprandial glucose (PPG) at 2 hours post-meal (7 mg/dL vs Fiasp) and was significantly different from Humalog (21 mg/dL) and Novo Rapid (29 mg/dL). Additionally, glucose excursions over the first 3 hours post-meal with URLi were comparable to those in healthy subjects. CONCLUSIONS: URLi demonstrated the fastest insulin absorption and the greatest numeric PPG-lowering effect compared to the other insulins tested. URLi more closely matched the early physiological glucose control observed in healthy subjects.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Younger Adults and Elderly Patients with Type 1 Diabetes Mellitus: A Randomised Controlled Trial.

BACKGROUND: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the pharmacokinetics, glucodynamics, safety, and tolerability of URLi and Humalog® in patients with type 1 diabetes mellitus (T1DM). METHODS: This was a phase I, two-period, randomised, double-blind, crossover glucose clamp study in younger adult (aged 18-45 years; n = 41) and elderly (aged ≥65 years; n = 39) patients with T1DM. At each dosing visit, patients received either URLi or Humalog (15 units subcutaneously) followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in serum 6 min faster, and exposure was 7.2-fold greater over the first 15 min postdose with URLi versus Humalog in both age groups. Exposure beyond 3 h postdose was 39-41% lower, and exposure duration was reduced by 72-74 min with URLi versus Humalog in both age groups. Onset of insulin action was 11-12 min faster, and insulin action was 3-fold greater over the first 30 min postdose with URLi versus Humalog in both age groups. Insulin action beyond 4 h postdose was 44-54% lower, and duration of action was reduced by 34-44 min with URLi versus Humalog in both age groups. Overall exposure and total insulin action remained similar for both treatments. URLi and Humalog were well tolerated. CONCLUSION: In patients with T1DM, URLi showed ultra-rapid pharmacokinetics and glucodynamics, with the differences between URLi and Humalog in elderly patients mirroring those in younger adults. ClinicalTrials.gov identifier: NCT03166124.

Pharmacokinetics and Glucodynamics of Ultra Rapid Lispro (URLi) versus Humalog® (Lispro) in Patients with Type 2 Diabetes Mellitus: A Phase I Randomised, Crossover Study.

BACKGROUND AND OBJECTIVE: Ultra rapid lispro (URLi) is a novel insulin lispro formulation developed to more closely match physiological insulin secretion and improve postprandial glucose control. This study compared the insulin lispro pharmacokinetics and glucodynamics, safety and tolerability of URLi and Humalog® after a single subcutaneous dose in patients with type 2 diabetes mellitus (T2DM). METHODS: This was a phase I, randomised, two-period, two-treatment, double-blind, crossover study in 38 patients with T2DM. At each dosing visit, patients received either 15 units of URLi or Humalog, followed by a 10 h automated euglycaemic clamp procedure. Serum insulin lispro and blood glucose were measured. RESULTS: Insulin lispro appeared in the serum 5 min faster (p < 0.0001) and exposure was 6.4-fold greater in the first 15 min (p < 0.0001) with URLi versus Humalog. Exposure beyond 3 h postdose was 26% lower and the duration of exposure was 51 min shorter with URLi versus Humalog. Onset of insulin action was 13 min faster (p < 0.0001) and insulin action was 4.2-fold greater within the first 30 min (p < 0.0001) with URLi versus Humalog. Insulin action beyond 4 h postdose was 20% lower (p = 0.0099) with URLi versus Humalog. Overall insulin lispro exposure and total glucose infused were similar for URLi and Humalog. Both treatments were well tolerated. CONCLUSIONS: This is the first study to investigate URLi in patients with T2DM using a euglycaemic clamp procedure. URLi demonstrated ultra-rapid pharmacokinetics and glucodynamics in patients with T2DM. CLINICALTRIALS. GOV IDENTIFIER: NCT03305822.

Efficacy outcomes from 3 clinical trials of edivoxetine as adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

OBJECTIVE: Three studies examined whether edivoxetine (a highly selective norepinephrine reuptake inhibitor) had efficacy as adjunctive therapy for patients with major depressive disorder (DSM-IV-TR) who were partial responders to selective serotonin reuptake inhibitor (SSRI) treatment of at least 6 weeks' duration. METHOD: Studies were 8-week randomized, placebo-controlled trials with a 3-week double-blind placebo lead-in phase, conducted from December 16, 2010, to October 21, 2013. Patients entered the double-blind adjunctive treatment phase if they met randomization criteria (< 25% improvement on Montgomery-Asberg Depression Rating Scale [MADRS] and MADRS total score ≥ 14); patients not randomized remained on adjunctive placebo. Study 1 compared fixed-dose edivoxetine (12 or 18 mg daily) + SSRI (N = 231 and N = 230, respectively) with placebo + SSRI (N = 240); study 2 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 232) and fixed-dose edivoxetine (6 mg daily) + SSRI (N = 226) with placebo + SSRI (N = 231); and study 3 compared flexible-dose edivoxetine (12-18 mg daily) + SSRI (N = 230) with placebo + SSRI (N = 219). The primary outcome was mean change from randomization baseline to week 8 in MADRS total score, analyzed using repeated measures analysis. RESULTS: Each trial failed to meet the primary and most of the secondary objectives. The least-squares mean changes in MADRS total score were as follows-study 1: -8.5 (edivoxetine 12 mg + SSRI), -8.7 (edivoxetine 18 mg + SSRI), and -7.8 (placebo + SSRI); study 2: -9.4 (edivoxetine 12-18 mg + SSRI), -9.6 (edivoxetine 6 mg + SSRI), and -9.4 (placebo + SSRI); and study 3: -8.7 (edivoxetine 12-18 mg + SSRI) and -8.5 (placebo + SSRI). CONCLUSIONS: Adjunctive edivoxetine treatment for patients with major depressive disorder who were partial responders to SSRIs did not significantly improve efficacy outcomes. TRIALS REGISTRATIONS: ClinicalTrials.gov identifiers: NCT01173601, NCT01187407, NCT01185340.

Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder.

OBJECTIVE: The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants. METHODS: A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs). RESULTS: The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994), respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07), respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001). The most common TEAEs (occurred ≥5% frequency) were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs -1.3 bpm, p<0.001). There were no clinically significant changes in laboratory measures. CONCLUSIONS: The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder.

Edivoxetine compared to placebo as adjunctive therapy to selective serotonin reuptake inhibitors in the prevention of symptom re-emergence in major depressive disorder.

OBJECTIVE: When patients with major depressive disorder (MDD) are partial responders to antidepressant therapy, adjunctive treatment with an agent that has a different mode of action may provide additional benefit. We investigated the efficacy of edivoxetine, a highly selective norepinephrine reuptake inhibitor (NRI), as adjunctive treatment to selective serotonin reuptake inhibitors (SSRIs) in the prevention of re-emergence of depressive symptoms in patients with MDD (ClinicalTrials.gov identifier: NCT01299272). METHODS: Adult outpatients with MDD who were partial responders to SSRI treatment (N = 1249) entered an open-label 8 week flexibly dosed (12-18 mg/day) adjunctive edivoxetine period. Patients who achieved remission (Montgomery-Åsberg Depression Rating Scale total score ≤10 at week 8) entered a 12 week open-label fixed-dose (12 mg or 18 mg/day) stabilization period, and those still in remission at each of weeks 18, 19, and 20 were randomized to continue treatment at the same dose of edivoxetine or switch to placebo for a 24 week double-blind withdrawal period. All patients remained on SSRI therapy throughout the study. The primary outcome was time to re-emergence of depressive symptoms during double-blind withdrawal. RESULTS: Two hundred and ninety-four patients were randomized to continue adjunctive edivoxetine and 292 were switched to adjunctive placebo. Comparing adjunctive edivoxetine with adjunctive placebo, differences were not significant for time to re-emergence of symptoms (Kaplan-Meier log-rank p = 0.485), rates of symptom re-emergence (9.9% vs 8.2%, p = 0.565) or rates of sustained remission (75.4% vs 76.7%, p = 0.771). Treatment-emergent adverse events were consistent with the noradrenergic mechanism of action. CONCLUSIONS: Edivoxetine failed to demonstrate superiority vs placebo as adjunctive treatment in the prevention of symptom re-emergence during maintenance treatment in SSRI partial responders with MDD. While no selective NRIs are approved for adjunctive treatment to SSRIs in MDD, the use of NRIs in this population is nonetheless accepted practice, but our data do not support the efficacy of this approach.

A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

BACKGROUND: This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. METHODS: Study design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6-18 mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. RESULTS: For the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. LIMITATIONS: Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. CONCLUSIONS: For patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression.

A randomized, double-blind study comparing LY2216684 and placebo in the treatment of major depressive disorder.

The efficacy, tolerability, and safety of LY2216684, a highly selective norepinephrine reuptake inhibitor, were studied in adult patients with major depressive disorder (MDD). This randomized, double-blind study compared flexible-dose LY2216684 6-18 mg once daily (N = 250) with placebo (N = 245) for 10 weeks acute therapy followed by 1 year LY2216684 treatment (results not reported here). Primary inclusion criteria consisted of GRID 17-item Hamilton Rating Scale for Depression total score ≥18 and Clinical Global Impressions-Severity score ≥4. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS) total score. Response was defined as a ≥50% reduction in MADRS score and remission as MADRS total score ≤10. Global functioning was assessed using the Sheehan Disability Scale (SDS). LY2216684-treated patients showed significant improvement from baseline on the MADRS total score compared with placebo-treated patients (-13.3 vs. -9.8, p < .001), and they had a significantly higher probability of achieving response (49.5%) and remission (29.7%) compared with placebo-treated patients (29.3% and 18.8%, respectively). For the SDS global functional impairment score, LY2216684 treatment resulted in significantly greater improvement compared with placebo treatment (p < .001). More LY2216684-treated than placebo-treated patients discontinued from the study because of an adverse event or death (9.6% vs. 1.6%, p ≤ .001). LY2216684 was associated with significant increases (p < .01) from baseline in systolic (3 mm Hg) and diastolic (4 mm Hg) blood pressure and pulse (10 bpm) compared with placebo. LY2216684 6-18 mg demonstrated significant efficacy and was tolerated in the treatment of MDD.

Case reports of postmarketing adverse event experiences with olanzapine intramuscular treatment in patients with agitation.

OBJECTIVE: Agitation is a medical emergency with increased risk for poor outcome. Successful treatment often requires intramuscular (IM) psychotropics. Safety data from the first 21 months of olanzapine IM, approved in the United States for the treatment of agitation associated with schizophrenia and bipolar disorder, are presented. METHOD: A Lilly-maintained safety database was searched for all spontaneous adverse events (AEs) reported in temporal association with olanzapine IM treatment. RESULTS: The estimated worldwide patient exposure to olanzapine IM from January 1, 2004, through September 30, 2005, was 539,000; 160 cases containing AEs were reported from patients with schizophrenia (30%), bipolar disorder (21%), unspecified psychosis (10%), dementia (8%), and depression (5%). Many reported concomitant treatment with benzodiazepines (39%) or other antipsychotics (54%). The most frequently reported events involved the following organ systems: central nervous (21%), cardiac (12%), respiratory (6%), vascular (6%), and psychiatric (5%). Eighty-three cases were considered serious, including 29 fatalities. In these fatalities, concomitant benzodiazepines or other antipsychotics were reported in 66% and 76% of cases, respectively. The most frequently reported events in the fatal cases involved the following organ systems: cardiovascular (41%), respiratory (21%), general (17%), and central nervous (10%). The majority of fatal cases (76%) included comorbid conditions and potentially clinically significant risk factors for AEs. CONCLUSIONS: Clinicians should use care when treating agitated patients, especially when they present with concurrent medical conditions and are treated with multiple medications, which may increase the risk of poor or even fatal outcomes. Clinicians should use caution when using olanzapine IM and parenteral benzodiazepines simultaneously.