Long-term tolerability and efficacy of golimumab in active non-radiographic axial spondyloarthritis: results from open-label extension.

OBJECTIVES: We report the open-label extension (OLE) of the GO-AHEAD study evaluating the long-term efficacy and safety of golimumab (GLM) in patients with non-radiographic axial spondyloarthritis (nr-axSpA). METHODS: Patients [both GLM- and placebo (PBO)-treated in the double-blind phase] received GLM 50 mg every 4 weeks during the OLE (36-week treatment; additional 8-week safety follow-up; GLM/GLM and PBO/GLM groups). All patients who entered and received ≥1 dose of study treatment in the OLE were included in the efficacy and safety analyses. The primary efficacy evaluations were the proportions of patients achieving 20% and 40% improvement in the ASAS criteria (ASAS20 and ASAS40, respectively). Responders' analyses were calculated using a non-responder imputation approach. RESULTS: Of 198 patients randomised, 189/198 (95.5%) entered the OLE; 174/198 patients (87.9%) completed all visits. Although the proportion of responders increased from week 16 to week 52 in the OLE in both GLM/GLM and PBO/GLM groups, the GLM/GLM group had a higher proportion of responders than the PBO/GLM group throughout the OLE from week 16 to week 52 (ASAS20: 71.1% to 83.9% vs 40.0% to 75.0%, respectively; ASAS40: 56.7% to 76.3% vs 23.0% to 59.4%, respectively; ASAS partial remission: 33.0% to 53.8% and 18.0% to 45.8%). In the OLE, the overall incidence of AEs was lower in the GLM/GLM vs PBO/GLM groups (41.9% and 54.2%). CONCLUSIONS: Sustained improvement in clinical efficacy was observed at 52 weeks in patients with nr-axSpA following GLM treatment. GLM was well tolerated and provided substantial long-term benefits to patients with nr-axSpA. TRIAL REGISTRATION: NCT01453725; United States National Library of Medicine clinical trials database; www.clinicaltrials.gov.

Efficacy and Safety of Ertugliflozin in Patients With Diabetes Mellitus Inadequately Controlled by Sulfonylurea Monotherapy: a Substudy of VERTIS CV.

INTRODUCTION: Sulfonylureas (SU) are commonly used antihyperglycemic agents. VERTIS CV was the cardiovascular outcome study for the sodium-glucose cotransporter 2 inhibitor ertugliflozin. Enrollment of patients in VERTIS CV occurred in two sequential cohorts (Cohort 1 and Cohort 2). METHODS: This substudy assessed the efficacy and safety of adding ertugliflozin to SU monotherapy. The primary endpoint was the change in HbA1c from baseline at 18 weeks. RESULTS: Among the 8246 patients who were randomized in VERTIS CV, 157 patients in Cohort 1 and 135 patients in Cohort 2 were on SU monotherapy at baseline. In the prespecified analysis (Cohort 1 only), the least squares (LS) mean HbA1c change from baseline for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was -  0.56%, -  0.91%, and -  0.78%, respectively (placebo-adjusted LS mean [95% CI] change: - 0.35% [-  0.72%, 0.02%]; -  0.22% [-  0.60%, 0.16%] for ertugliflozin 5 and 15 mg, respectively; p > 0.05 for both). In a post-hoc analysis that included Cohorts 1 and 2 (N = 292), the LS mean HbA1c change from baseline at week 18 for placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg was -  0.31%, - 0.77%, and -  0.68%, respectively (placebo-adjusted change: -  0.46% [-  0.73%, -  0.18%]; -  0.37% [-  0.66%, -  0.09%]; p = 0.001 and 0.01 for ertugliflozin 5 and 15 mg, respectively). In Cohort 1, adverse events were reported in 45.8%, 47.3%, and 25.9% of patients with placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg. The incidence rates of symptomatic hypoglycemia were 0.0%, 5.5%, and 3.7%, respectively, with no cases of severe hypoglycemia. The safety profile was similar for Cohorts 1 and 2 combined. CONCLUSION: The addition of ertugliflozin to SU monotherapy reduced HbA1c but did not result in significant placebo-adjusted reductions from baseline according to the prespecified primary analysis (n = 157); however, in a post-hoc analysis with a larger patient population (n = 292), significant and clinically relevant HbA1c reductions were observed. Ertugliflozin was generally well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01986881.

Colectomy Incidence Rates in Five-Year Data From the Observational Postmarketing Ulcerative Colitis Study of Originator Infliximab.

BACKGROUND: This analysis of the Observational Postmarketing Ulcerative Colitis Study examined incidence rates of colectomy in patients with ulcerative colitis who received originator infliximab (IFX) or conventional therapies (ConvRx) as per their treating physician. METHODS: Cox proportional hazards models compared time to colectomy for both treatment groups. A secondary analysis examined colectomy incidence rates based on IFX exposure timing (defined by a 90-day window after the last IFX dose date). RESULTS: Of 2239 patients with data, 1059 enrolled in IFX and 1180 enrolled in ConvRx (including 296 patients who switched to IFX). Patients in the IFX group had more severe disease at baseline vs the ConvRx group (percentage with baseline partial Mayo score 7-9: 46.0% vs 30.5%, respectively). During 5 years of follow-up, 271 patients (12.1% of enrolled patients) had colectomy. Enrollment in the IFX group was associated with a higher risk of colectomy (hazard ratio = 3.12; 95% confidence interval, 2.25-4.34; P < 0.001) compared with enrollment in the ConvRx group. A total of 174 colectomies occurred in the IFX group, but 97 of these colectomies occurred ≥90 days after the last IFX dose date. CONCLUSIONS: Colectomy was reported at a higher rate in the IFX group than in the ConvRx group, although patients in the IFX group had more severe disease at baseline and most of the colectomies occurred after patients had been off of IFX for ≥90 days.

Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis.

Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain. Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes. Data Sources: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020. Study Selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials. Data Extraction and Synthesis: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model. Main Outcomes and Measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials. Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction). Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.

Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.

BACKGROUND: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established. METHODS: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure. RESULTS: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo. CONCLUSIONS: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).

Efficacy and safety of ertugliflozin in older patients with type 2 diabetes: A pooled analysis of phase III studies.

AIM: To assess the efficacy and safety of ertugliflozin in older patients with type 2 diabetes (T2D). MATERIALS AND METHODS: This is a post hoc analysis of patients with T2D aged less than 65 years and those aged 65 years or older who participated in randomized, double-blind, phase III studies of ertugliflozin. Efficacy was evaluated in a pooled analysis of three placebo-controlled studies (ertugliflozin monotherapy and add-on therapy). Safety was evaluated in a pooled analysis of seven placebo- and active-controlled studies (including those used for efficacy). Least-squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs). RESULTS: In participants aged less than 65 years, the placebo-adjusted mean changes from baseline in HbA1c, BW and SBP with ertugliflozin 5 and 15 mg at week 26 were -0.9% and -1.0%, -1.9 and -1.8 kg, and -3.7 and -3.6 mmHg, respectively; in participants aged 65 years or older they were -0.6% and -0.8%, -1.9 and -2.2 kg, and -2.7 and -3.4 mmHg, respectively. The incidences of AEs, serious AEs, discontinuations and deaths in participants aged less than 65 years and those aged 65 years or older were generally similar across the treatment groups. In patients aged 65 years or older the incidences of volume depletion AEs and genital mycotic infection were higher with ertugliflozin than with non-ertugliflozin. CONCLUSIONS: Ertugliflozin improved glycaemic control, BW and SBP in younger and older individuals with T2D and was generally well tolerated in both groups.

Safety of Ertugliflozin in Patients with Type 2 Diabetes Mellitus: Pooled Analysis of Seven Phase 3 Randomized Controlled Trials.

INTRODUCTION: The sodium-glucose cotransporter 2 (SGLT2) inhibitor ertugliflozin is approved for the treatment of adults with type 2 diabetes mellitus (T2DM). This analysis was conducted on safety data pooled from phase 3 studies using ertugliflozin 5 mg or 15 mg versus placebo or an active comparator. METHODS: The placebo pool (n = 1544) comprised data from three similarly designed 26-week placebo-controlled studies. The broad pool (n = 4849) comprised these three placebo-controlled studies plus four placebo- or active-controlled studies with treatment durations of up to 104 weeks. RESULTS: In the placebo pool, there were no notable differences across groups in the incidence of adverse events (AEs), serious AEs, or AEs resulting in discontinuation from study medication, while associations were observed with genital mycotic infection in both females (3.0%, 9.1%, and 12.2% in the placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg groups, respectively) and males (0.4%, 3.7%, 4.2%), thirst (0.2%, 1.3%, 1.0%), and increased urination (1.0%, 2.7%, 2.4%). In the broad pool, volume depletion was increased with ertugliflozin in patients with estimated glomerular filtration rate < 60 ml/min/1.73 m2, aged ≥ 65 years, or who were taking diuretics. Ertugliflozin was not associated with increased urinary tract infection, fracture, hypoglycemia, pancreatitis, renal or hepatic injury, hypersensitivity, malignancy, or venous thromboembolism. Small numbers of patients were reported with lower limb amputation [0.1% (non-ertugliflozin group), 0.2% (ertugliflozin 5 mg), 0.5% (ertugliflozin 15 mg)]. There were three cases of ketoacidosis (all ertugliflozin 15 mg) and no cases of Fournier's gangrene. CONCLUSION: This pooled analysis showed that ertugliflozin was generally well tolerated in a large population of patients with T2DM with and without moderate renal impairment who were taking a range of background diabetes medications including insulin and insulin secretagogs, with results that are generally consistent with those for other SGLT2 inhibitors. TRIAL REGISTRATION: Clinicaltrials.gov indentifier, NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

Efficacy and safety of ertugliflozin in Hispanic/Latino patients with type 2 diabetes mellitus.

Objective: To assess the efficacy and safety of ertugliflozin in Hispanic/Latino patients with type 2 diabetes (T2DM).Methods: Analysis of data from Hispanic/Latino patients who participated in randomized, double-blind phase III studies. Ertugliflozin efficacy was evaluated when initiated as a single agent (as monotherapy or add-on therapy) and when initiated in combination with sitagliptin. Least-squares mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight (BW), and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).Results: Analyses included 1178 Hispanic/Latino patients. In a pooled analysis of three placebo-controlled studies where ertugliflozin was initiated as a single agent, the placebo-corrected change from baseline in HbA1c at week 26 for ertugliflozin 5 and 15 mg was -0.8 and -1.0%, respectively. In an active-comparator study, when initiated as a single agent, the change from baseline in HbA1c at week 52 was -0.5, -0.7, and -0.5% for ertugliflozin 5 mg, ertugliflozin 15 mg, and glimepiride, respectively. In a placebo-controlled study, when initiated in combination with sitagliptin, the placebo-corrected change from baseline in HbA1c at week 26 for ertugliflozin 5 mg/sitagliptin and ertugliflozin 15 mg/sitagliptin was -1.3 and -1.6%, respectively. In an active-comparator study, when initiated in combination with sitagliptin, the change from baseline in HbA1c at week 26 was -1.4, -1.6, and -0.9 for ertugliflozin 5 mg/sitagliptin, ertugliflozin 15 mg/sitagliptin, and sitagliptin alone, respectively. Reductions in BW and SBP were observed with ertugliflozin as a single agent or combined with sitagliptin. The incidences of overall and prespecified AEs in Hispanic/Latino patients were generally consistent with the known safety profile of ertugliflozin.Conclusion: Ertugliflozin, administered as a single agent or as a combination with sitagliptin, improved HbA1c, BW, and SBP. Ertugliflozin was generally well-tolerated in Hispanic/Latino patients with T2DM. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.

Efficacy and safety of ertugliflozin across racial groups in patients with type 2 diabetes mellitus.

Objective: To assess the efficacy and safety of the sodium-glucose cotransporter 2 inhibitor ertugliflozin across racial groups in patients with type 2 diabetes mellitus (T2DM).Methods: Pooled analysis of data from randomized, double-blind studies in the ertugliflozin phase III development program. Seven placebo- and comparator-controlled studies were used to assess safety (N = 4859) and three placebo-controlled studies were used to assess efficacy (N = 1544). Least-squares (LS) mean change from baseline was calculated for glycated hemoglobin (HbA1c), body weight and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events (AEs).Results: At Week 26, ertugliflozin provided a greater reduction in HbA1c, body weight and SBP versus placebo in all racial subgroups. The placebo-adjusted LS mean change (95% confidence interval) from baseline in HbA1c was -0.8% (-1.0, -0.7) and -1.0% (-1.1, -0.8) with ertugliflozin 5 mg and 15 mg, respectively, in the White subgroup, -0.7% (-1.2, -0.2) and -0.8% (-1.3, -0.3) in the Black subgroup, and -0.8% (-1.1, -0.5) and -1.0% (-1.3, -0.8) in the Asian subgroup. The incidences of overall AEs, serious AEs and AEs leading to discontinuation from study medication were similar between the ertugliflozin 5 mg, 15 mg and non-ertugliflozin groups within each racial subgroup. The incidence of female genital mycotic infection (GMI) was higher with ertugliflozin than non-ertugliflozin across all racial subgroups. The incidence of male GMI was higher with ertugliflozin than non-ertugliflozin in the White sub-group; however, there were few male GMI events in the non-White subgroups.Conclusions: In patients with T2DM, treatment with ertugliflozin improved HbA1c, body weight and SBP across all racial subgroups. Ertugliflozin had a generally similar safety profile across racial subgroups and was generally well tolerated. Clinicaltrials.gov identifiers: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, and NCT02226003.

Efficacy and safety of ertugliflozin in East/Southeast Asian patients with type 2 diabetes mellitus.

AIM: Post-hoc analysis of the efficacy and safety of ertugliflozin in East/Southeast (E/SE) Asian patients with type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: Efficacy evaluations used data from randomized, double-blind, phase 3 studies: a pool of two 26-week placebo-controlled studies and one 52-week active-comparator (glimepiride) study. Least squares mean change from baseline was calculated for HbA1c, fasting plasma glucose (FPG), body weight (BW) and systolic blood pressure (SBP). Safety evaluation included overall and prespecified adverse events based on pooled data (broad pool) from seven phase 3 studies (including studies in the efficacy analysis). RESULTS: Among 161 E/SE Asian patients in the placebo pool (ertugliflozin, n = 106), ertugliflozin reduced HbA1c, FPG, BW and SBP from baseline at week 26. The placebo-adjusted changes from baseline for ertugliflozin 5 and 15 mg were: HbA1c, -0.9% and -1.0%; BW, -2.1 and -1.9 kg; and SBP, -3.3 and -3.5 mmHg, respectively. Among 174 E/SE Asian patients in the active-comparator study (ertugliflozin, n = 118), HbA1c changes from baseline at week 52 were -0.6%, -0.6% and -0.7% for ertugliflozin 5 mg, 15 mg and glimepiride, respectively. Ertugliflozin 5 and 15 mg reduced BW from baseline by -4.3 and -4.1 kg, respectively, and SBP by -7.4 and -9.3 mmHg, respectively, compared with glimepiride. Safety findings were generally consistent with overall ertugliflozin safety data published to date. CONCLUSIONS: Treatment with ertugliflozin was associated with reductions in HbA1c, FPG, BW and SBP, and was generally well tolerated in E/SE Asian patients with T2DM. ClinicalTrials.gov identifier: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, NCT02226003.

Efficacy of ertugliflozin in monotherapy or combination therapy in patients with type 2 diabetes: A pooled analysis of placebo-controlled studies.

BACKGROUND: This pooled analysis assessed the efficacy of ertugliflozin versus placebo as monotherapy or with other antihyperglycaemic agents across patient subgroups defined by demographic and disease characteristics. METHODS: Data from three phase III randomised, placebo-controlled, double-blind studies (NCT01958671, NCT02033889 and NCT02036515) with similar designs and populations were pooled (N = 1544). RESULTS: At Week 26, placebo-adjusted least squares mean changes from baseline in glycated haemoglobin with ertugliflozin 5 and 15 mg were -0.8% (95% confidence interval: -0.9, -0.7) and -0.9% (-1.0, -0.8), respectively. Reductions were consistent across subgroups. Placebo-adjusted least squares mean changes in body weight were -1.8 kg (-2.2, -1.4) for both ertugliflozin doses; for systolic blood pressure, these were -3.4 mmHg (-4.8, -2.0) and -3.5 mmHg (-4.9, -2.0) for ertugliflozin 5 and 15 mg, respectively. Higher proportions of patients receiving ertugliflozin had glycated haemoglobin <7.0%, weight loss ⩾5% and systolic blood pressure <130 mmHg versus placebo. Ertugliflozin and placebo safety profiles were similar, including incidences of hypoglycaemia, urinary tract infection and hypovolaemia. Genital mycotic infection and adverse events related to osmotic diuresis were more common with ertugliflozin. CONCLUSION: Ertugliflozin demonstrated efficacy as monotherapy or with other antihyperglycaemic agents in patients with different demographic and disease characteristics and was generally well tolerated.

Safety and efficacy of ertugliflozin in Asian patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: VERTIS Asia.

AIM: Phase III, randomized, double-blind study evaluating the efficacy and safety of ertugliflozin in Asian patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin, including evaluation in the China subpopulation. MATERIALS AND METHODS: A 26-week, double-blind study of 506 Asian patients (80.2% from mainland China), randomized 1:1:1 to placebo, ertugliflozin 5- or 15 mg, was performed. Primary endpoint was change from baseline in HbA1c at week 26. Secondary endpoints were change from baseline at week 26 in fasting plasma glucose (FPG), body weight (BW), systolic/diastolic blood pressure (SBP/DBP), and proportion of patients with HbA1c <7.0%. Hypotheses for the primary endpoint and FPG and BW secondary endpoints were tested in the China subpopulation. RESULTS: At week 26, least squares mean (95% CI) change from baseline HbA1c was significantly greater with ertugliflozin 5- and 15 mg versus placebo: -1.0% (-1.1, -0.9), -0.9% (-1.0, -0.8), -0.2% (-0.3, -0.1), respectively. Ertugliflozin significantly reduced FPG, BW and SBP. Reductions in DBP with ertugliflozin were not significant. At week 26, 16.2%, 38.2% and 40.8% of patients had HbA1c <7.0% with placebo, ertugliflozin 5- and 15 mg, respectively. 59.3%, 56.5% and 53.3% of patients experienced adverse events with placebo, ertugliflozin 5- and 15 mg, respectively. Incidence of symptomatic hypoglycaemia was higher for ertugliflozin 15 mg vs placebo. Results in the China subpopulation were consistent. CONCLUSIONS: Ertugliflozin significantly improved glycaemic control and reduced BW and SBP in Asian patients with T2DM. Ertugliflozin was generally well-tolerated. Results in the China subpopulation were consistent with the overall population. ClinicalTrials.gov: NCT02630706.

Five-year Safety Data From OPUS, a European Observational Safety Registry for Adults With Ulcerative Colitis Treated With Originator Infliximab [Remicade®] or Conventional Therapy.

BACKGROUND AND AIMS: The Observational Postmarketing Ulcerative colitis Study [OPUS] was conducted to obtain the first long-term [5 years] safety data assessing treatment with originator infliximab versus conventional therapies in patients with ulcerative colitis [UC] in real-world clinical practice. METHODS: The OPUS registry was a prospective, non-randomised, observational study that measured adverse events in nine prespecified categories of interest in UC patients whose treatment with either originator infliximab or conventional therapy [defined as initiation or dose-increase of corticosteroids and/or immunosuppressants] was determined by their treating physician. RESULTS: Data for 2239 patients were available: N = 1180 enrolled to conventional therapy [including N = 296 who switched to originator infliximab during follow-up] and N = 1059 enrolled to originator infliximab. Patients in the originator infliximab group, compared with the conventional therapy group, had more severe disease at baseline, based on partial Mayo score [PMS]: 46.0% of patients in the originator infliximab group had severe disease (PMS of 7-9 [out of 9]), compared with 30.5% in the conventional therapy group. In adjusted time-to-event analyses, enrolment into the originator infliximab group was associated with a higher risk of serious infection (hazard ratio = 1.98 [95% confidence interval: 1.34, 2.91; p <0.001]) compared with enrolment into the conventional therapy group. No notable risk differences between groups were identified for haematological disorder, autoimmune disorder, malignancy/lymphoproliferative disorder, hepatobiliary disorder or fatality. CONCLUSIONS: UC patients treated with infliximab had higher risk for serious infection, compared with conventional therapies. No new safety concerns were observed with originator infliximab in the OPUS registry. [ClinicalTrials.gov: NCT00705484.].

Results of VERTIS SU extension study: safety and efficacy of ertugliflozin treatment over 104 weeks compared to glimepiride in patients with type 2 diabetes mellitus inadequately controlled on metformin.

Objective: To assess the safety and efficacy of ertugliflozin over 104 weeks in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin. Methods: In this double-blind, multicenter, randomized, phase III study (VERTIS SU; NCT01999218), adults with T2DM and glycated hemoglobin (HbA1c) 7.0-9.0% on metformin ≥1500 mg/day received ertugliflozin 5 mg or 15 mg, or glimepiride. The primary efficacy time point was Week 52; double-blinded treatment continued until Week 104. Results: Baseline characteristics of randomized, treated patients (n = 1315) were similar across groups (mean age 58.2 years, HbA1c 7.8%); 76.4% completed the study; 61.6% completed on study medication. Mean glimepiride dose at 104 weeks was 3.5 mg/day. At Week 104, least squares mean change from baseline in HbA1c (95% confidence intervals) were -0.3% (-0.4, -0.2), -0.4% (-0.5, -0.3) and -0.4% (-0.5, -0.3) for ertugliflozin 5 mg, 15 mg, and glimepiride, respectively. Ertugliflozin provided sustained reductions in body weight and systolic blood pressure (SBP) over 104 weeks. The incidence of adverse events (AEs) and serious AEs was similar across groups. The incidence of symptomatic hypoglycemia was 3.8%, 6.4% and 22.1% in the ertugliflozin 5 mg, 15 mg, and glimepiride groups, respectively. Genital mycotic infections were reported in 5.3%, 2.6% and 0% of men, respectively, and 9.2%, 12.3% and 1.4% of women, respectively. The incidence of urinary tract infection and hypovolemia AEs was similar across groups. Conclusions: Ertugliflozin was well tolerated and provided clinically meaningful glycemic control and durable reductions in body weight and SBP over 104 weeks.

Long-term efficacy and safety of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy: 104-week VERTIS MET trial.

AIM: To evaluate the long-term efficacy and safety of ertugliflozin in adults with type 2 diabetes mellitus inadequately controlled on metformin. MATERIALS AND METHODS: A 104-week Phase III, randomized double-blind study with a 26-week placebo-controlled period (Phase A) and a 78-week period (Phase B) where blinded glimepiride was added to non-rescued placebo participants with fasting fingerstick glucose ≥6.1 mmol/L. Results through week 104 are reported. RESULTS: Mean (standard error) change in HbA1c from baseline was -0.7% (0.07) and -1.0% (0.07) at week 52; -0.6% (0.08) and -0.9% (0.08) at week 104 for ertugliflozin 5 and 15 mg. At week 52, 34.8% and 36.6% participants had HbA1c <7.0%, and 24.6% and 33.7% at week 104, for ertugliflozin 5 and 15 mg. Ertugliflozin reduced fasting plasma glucose (FPG), body weight and systolic blood pressure (SBP) from baseline through week 104. The incidence of female genital mycotic infections (GMIs) was higher with ertugliflozin, and symptomatic hypoglycaemia was lower for ertugliflozin versus placebo/glimepiride. Minimal bone mineral density (BMD) changes were observed, similar to placebo/glimepiride, except at total hip where reduction in BMD was greater with ertugliflozin 15 mg versus placebo/glimepiride: difference in least squares means (95% CI) -0.50% (-0.95, -0.04) at week 52 and -0.84% (-1.44, -0.24) at week 104. CONCLUSIONS: Ertugliflozin maintained improvements from baseline in HbA1c, FPG, body weight and SBP through week 104. Ertugliflozin was well tolerated, with non-clinically relevant changes in BMD. Compared with placebo/glimepiride, ertugliflozin increased female GMIs, but reduced the incidence of symptomatic hypoglycaemia. ClinicalTrials.gov Identifier: NCT02033889.

Continuous Clinical Response Is Associated With a Change of Disease Course in Patients With Moderate to Severe Ulcerative Colitis Treated With Golimumab.

Background: Responders to induction treatment sustain continuous clinical response (CCR) through 1 year in about 50% of patients in PURSUIT-M trial with golimumab maintenance in ulcerative colitis (UC). This post hoc analysis of PURSUIT-M describes the 1-year clinical, endoscopic, quality of life (QoL), and biomarker and 4-year clinical outcome in patients with sustained response to golimumab therapy for UC. Methods: We compared clinical, endoscopic, QoL, and calprotectin outcomes in CCR and non-CCR patients through 54 weeks in PURSUIT-M. Persistence on golimumab therapy and clinical response at 4 years was assessed for CCR and non-CCR patients. The relationship of colectomy with CCR status was determined. Results: Among patients receiving golimumab maintenance, greater proportions of patients with vs without CCR at week 54 achieved clinical remission (67.1% vs 1.9%), corticosteroid-free remission (61.6% vs 1.9%), endoscopic remission (Mayo endoscopy score 0 [47.9% vs 1.3%]), and normal QoL (inflammatory bowel disease questionnaire score ≥170 [75.0% vs 24.4%]). CCR but not non-CCR patients maintained normalized calprotectin levels during maintenance. Among patients who entered the long-term extension study, a greater proportion of patients with vs without CCR maintained PGA 0 through week 216 (58% vs 42%). Colectomy was performed in 47 induction nonresponders and in 13 induction responders. None of the patients going onto colectomy achieved CCR through 54 weeks in PURSUIT-M. Conclusions: Continuous clinical response is associated with favorable short- and long-term clinical, endoscopic, QoL, and biomarker responses that may result in changing the course of disease and may prevent colectomy in patients with moderate to severe UC treated with golimumab. 10.1093/ibd/izy229_video1izy229.video15806022773001.

How 4 Companies Became One: Co-development Under an Outsourced Model With Focus on Phase 3 Analysis and Reporting Deliverables.

With the growth in co-development deals between pharmaceutical companies and the increased use of contract research organizations (CROs) in drug development, more and more employees are encountering projects that require working across different companies. Navigating the mix of corporate cultures as well as variations in standards and procedures can lead to unanticipated challenges and delays. The development of ertugliflozin, a recently approved medicine for type 2 diabetes mellitus, involved both co-development and CRO engagement across 4 companies. Challenges to combining processes and systems across the 4 companies were encountered and resolved. Early decisions for adoption of standards and processes as well as the organization of committees and communication pathways were key to the success of this ambitious program. Here we share our experiences and lessons learned with respect to the analysis and reporting of clinical trial results.

Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).

BACKGROUND: Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline. METHODS: Patients ≥40 years old with T2DM (HbA1c 7.0-10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy. RESULTS: 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients. CONCLUSION: The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD.

Ertugliflozin and Sitagliptin Co-initiation in Patients with Type 2 Diabetes: The VERTIS SITA Randomized Study.

INTRODUCTION: Ertugliflozin is an oral sodium-glucose cotransporter 2 inhibitor that is being developed to treat type 2 diabetes mellitus (T2DM). This study assessed the efficacy and safety of co-initiation of ertugliflozin and sitagliptin compared with placebo in patients with T2DM inadequately controlled on diet and exercise. METHODS: In this phase III, randomized, double-blind, multicenter, placebo-controlled 26-week study (NCT02226003), patients with T2DM and glycated hemoglobin (HbA1c) 8.0-10.5% on diet/exercise were randomized 1:1:1 to ertugliflozin 5 mg once daily (QD) and sitagliptin 100 mg QD (E5/S100), ertugliflozin 15 mg QD and sitagliptin 100 mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26. RESULTS: The mean baseline HbA1c of the randomized patients (n = 291) was 8.9%. At week 26, both ertugliflozin/sitagliptin treatments provided significant reductions from baseline in HbA1c compared with placebo [least squares mean HbA1c change (95% confidence intervals) from baseline was - 0.4% (- 0.7, - 0.2), - 1.6% (- 1.8, - 1.4), and - 1.7% (- 1.9, - 1.5) for placebo, E5/S100, and E15/S100, respectively]. At week 26, 8.3%, 35.7%, and 31.3% of patients receiving placebo, E5/S100, and E15/S100, respectively, had HbA1c < 7.0%. Significant reductions in fasting plasma glucose, 2-h post-prandial glucose, body weight, and systolic blood pressure were observed with both ertugliflozin/sitagliptin groups compared with placebo. The incidence of adverse events (AEs) was similar across the groups. The incidences of the pre-specified AEs of urinary tract infection, genital mycotic infection, symptomatic hypoglycemia, and hypovolemia were low and not meaningfully different across groups. CONCLUSION: Co-initiation of ertugliflozin with sitagliptin in patients with T2DM inadequately controlled on diet and exercise provided a clinically meaningful improvement in glycemic control over 26 weeks. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT02226003.

Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: The VERTIS SITA2 placebo-controlled randomized study.

AIMS: To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin. MATERIALS AND METHODS: In this double-blind randomized study (Clinicaltrials.gov NCT02036515), patients (glycated haemoglobin [HbA1c] 7.0% to 10.5% [53-91 mmol/mol] receiving metformin ≥1500 mg/d and sitagliptin 100 mg/d; estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 ) were randomized to ertugliflozin 5 mg once-daily, 15 mg once-daily or placebo. The primary efficacy endpoint was change from baseline in HbA1c at Week 26; treatment was continued until Week 52. RESULTS: A total of 464 patients were randomized (mean baseline HbA1c, 8.0% [64.3 mmol/mol]; eGFR, 87.9 mL/min/1.73 m2 ). After 26 weeks, placebo-adjusted least squares (LS) mean changes in HbA1c from baseline were -0.7% (-7.5 mmol/mol) and -0.8% (-8.3 mmol/mol) for ertugliflozin 5 and 15 mg, respectively (both P < .001); 17.0%, 32.1% and 39.9% of patients receiving placebo, ertugliflozin 5 mg or ertugliflozin 15 mg, respectively, had HbA1c <7.0% (53 mmol/mol). Significant reductions in fasting plasma glucose, body weight (BW) and systolic blood pressure (SBP) were observed with ertugliflozin relative to placebo. The positive effects of ertugliflozin on glycaemic control, BW and SBP were maintained through Week 52. A higher incidence of genital mycotic infections was observed in male and female patients receiving ertugliflozin (3.7%-14.1%) vs placebo (0%-1.9%) through Week 52. The incidence of urinary tract infections, symptomatic hypoglycaemia and hypovolaemia adverse events were not meaningfully different across groups. CONCLUSIONS: Ertugliflozin added to metformin and sitagliptin was well-tolerated, and provided clinically meaningful, durable glycaemic control, BW and SBP reductions vs placebo over 52 weeks.