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Summary: This post hoc analysis of a randomized, double-blind study of postmenopausal women with osteoporosis found that there were early increases in bone turnover markers and decreases in bone mineral density after discontinuation of long-term alendronate. These findings might help guide treatment decisions, including monitoring after alendronate withdrawal. Introduction: The short-term effects of discontinuing long-term bisphosphonates are poorly characterized. This post hoc analysis investigated 1–12-month changes in bone mineral density (BMD) and bone turnover markers (BTM) after alendronate (ALN) discontinuation. Methods: Data were from a randomized, double-blind trial of MK-5442 (calcium-sensing receptor antagonist) following oral bisphosphonates, with placebo and continued ALN controls (ClinicalTrials.gov NCT00996801). Postmenopausal women with osteoporosis had received oral bisphosphonate (≥ 3–4 preceding years; ALN for the 12 months pre-screening), continuing on ALN 70 mg/week (n = 87) or placebo (n = 88). Results: At 12 months, least-squares mean percent changes from baseline BMD (placebo vs. ALN) were lumbar spine (LS): – 0.36 vs. 1.29, total hip: – 1.44 vs. 0.46, and femoral neck (FN): – 1.26 vs. – 0.08 (all P < 0.05). BTM levels increased by 1–3 months, to 12 months, with placebo vs. ALN (P < 0.001). FN BMD decline was greater in the placebo subgroup with higher urinary N-terminal cross-linked telopeptides of type I collagen/creatinine [uNTx/Cr] (P < 0.01), and higher serum N-terminal pro-peptide of type 1 collagen [P1NP] levels (P < 0.05), at baseline. There was a trend toward greater FN BMD loss with higher BTM levels at 3 and/or 6 months. Younger age and higher LS BMD at baseline were associated with greater LS BMD loss at 12 months (P = 0.04 and < 0.01, respectively); higher baseline FN BMD predicted greater FN BMD loss (P = 0.04). Conclusion: Early changes in BTM levels and BMD were observed after discontinuation of long-term ALN. Further characterization of factors associated with patients’ risk of bone loss upon bisphosphonate discontinuation is warranted.

Background Results from a phase III, randomized, double-blind, active comparator-controlled, parallel-group trial evaluating fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) found that a single-day, triple-antiemetic fosaprepitant regimen resulted in a significantly higher proportion of patients achieving a complete response (CR; no vomiting or rescue medication use) in the delayed phase (25–120 h after chemotherapy initiation), compared with a 3-day control regimen (ClinicalTrials.gov, NCT01594749). As the risk for CINV is dependent on chemotherapy regimen and generally guided by tumor type, this post hoc analysis evaluated the efficacy and safety of this regimen by cancer subpopulations (gastrointestinal [GI] or colorectal, lung, breast, and gynecologic cancers). Methods Subjects with confirmed cancer who were naive to highly and moderately emetogenic chemotherapy (HEC and MEC) and were scheduled to receive intravenous (IV) anthracycline-cyclophosphamide (AC)–based MEC on the first day of chemotherapy were randomly assigned to receive oral ondansetron and oral dexamethasone plus either a single IV dose of fosaprepitant 150 mg (fosaprepitant regimen) or placebo (control regimen). The primary efficacy end point was the proportion of subjects achieving CR in the delayed phase. CR rates in the overall and acute phases (0–120 h and 0–24 h after MEC initiation, respectively) were assessed as secondary end points. Safety and tolerability were also assessed. Results CR rates in the delayed phase favored the fosaprepitant regimen over the control regimen across the GI/colorectal, lung, breast, and gynecologic cancer subgroups (range, 6.2–22%); similar findings were observed for CR in the overall phase. CR in the acute phase was high for all groups (≥87%). The fosaprepitant regimen was well tolerated in all cancer subgroups. Conclusions This post hoc analysis indicated that a single-day fosaprepitant regimen was effective in preventing CINV in patients receiving MEC, regardless of cancer type. Trial registration ClinicalTrials.govNCT01594749, registered May 9, 2012.

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.

PURPOSE To identify factors associated with chemotherapy-induced vomiting (CIV) control in pediatric patients receiving highly emetogenic chemotherapy (HEC) or moderately emetogenic chemotherapy (MEC). MATERIALS AND METHODS An individual, patient‐level, pooled analysis was performed using data from five clinical trials of aprepitant or fosaprepitant in pediatric patients receiving HEC or MEC. The proportion of individuals who experienced no vomiting (complete CIV control) during the phase of interest was the primary study end point. The association of acute-phase complete CIV control (from first chemotherapy dose to 24 hours after the last chemotherapy dose of the chemotherapy block) with age, sex, race, cancer type, acute-phase duration, and antiemetic regimen was examined. Association of the same factors and acute-phase complete CIV control with complete CIV control in the delayed phase (end of acute phase until ≤ 96 hours later) was examined. RESULTS A total of 735 patients (mean age, 8.9 years; range, 0.3 to 17.9 years) were included in the acute-phase analysis. Acute-phase complete CIV control was less likely in older patients (relative risk [RR], 0.97 per year; 95% CI, 0.96 to 0.98 per year) and longer acute-phase duration (RR, 0.89 per day; 95% CI, 0.84 to 0.94 per day). Receipt of ondansetron plus aprepitant or fosaprepitant was associated with a higher likelihood of acute-phase complete CIV control versus ondansetron alone (RR, 1.28; 95% CI, 1.09 to 1.50). Delayed-phase complete CIV control was more likely in patients with acute-phase complete CIV control (RR, 1.19; 95% CI, 1.06 to 1.34) and in those who received aprepitant or fosaprepitant. CONCLUSION Younger age, shorter acute-phase duration, and antiemetic regimen were associated with acute-phase complete CIV control in pediatric patients receiving HEC or MEC. Acute-phase complete CIV control and antiemetic regimen were associated with delayed-phase complete CIV control.

Introduction This post hoc exploratory analysis examined the effects of ertugliflozin on liver enzymes in patients with type 2 diabetes mellitus (T2DM). Methods Data were pooled from seven randomized, double-blind VERTIS phase 3 trials that evaluated ertugliflozin (5 mg and 15 mg) versus non-ertugliflozin (placebo, glimepiride, or sitagliptin) treatment in patients with T2DM. Change from baseline at week 52 of treatment in alanine and aspartate aminotransferase (ALT and AST, respectively) serum levels (overall and categorized into tertiles by baseline ALT and AST), Fibrosis-4 Index (FIB-4), glycated hemoglobin (HbA1c), and body weight were evaluated, along with the association between changes in ALT and AST and changes in HbA1c and body weight by treatment. Results Baseline characteristics were balanced across treatment groups (ertugliflozin 5 mg, n = 1716; ertugliflozin 15 mg, n = 1693; non-ertugliflozin, n = 1450). At week 52 of treatment, serum levels of ALT and AST were reduced in patients in the ertugliflozin treatment groups (5 and 15 mg, respectively) compared with those in the non-ertugliflozin group. The comparator-adjusted mean (95% confidence interval [CI]) difference in change from baseline at week 52 for ALT was − 3.35 (− 4.40, − 2.31) IU/L for ertugliflozin 5 mg and − 4.08 (− 5.13, − 3.03) IU/L for ertugliflozin 15 mg; for AST, the respective values were − 1.81 (− 2.50, − 1.11) IU/L and − 2.12 (− 2.82, − 1.42) IU/L. The effects of ertugliflozin were detected across all baseline ALT and AST tertiles, with the highest tertile showing the greatest treatment differences. No meaningful differences were observed between treatment groups for FIB-4. Changes in ALT and AST showed a weak but statistically significant association with changes in HbA1c and body weight in all treatment groups. Conclusions Treatment with ertugliflozin resulted in a reduction in the levels of hepatic transaminases compared with the non-ertugliflozin group after 52 weeks of treatment. Changes in body weight and HbA1c contributed at least in part to the effects of ertugliflozin on liver enzymes. Trial Registration Clinicaltrials.gov registry numbers: NCT02033889, NCT01958671, NCT02036515, NCT01986855, NCT02099110, NCT02226003, NCT01999218.

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.

Aims/hypothesisThis study aimed to evaluate the effect of ertugliflozin, a sodium–glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.govNCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population.MethodsPost hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks.ResultsOverall, mean (SD) baseline eGFR was 88.2 (18.8) ml min−1(1.73 m)−2and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were −2.3, −2.7 and −0.7 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were −0.2, 0.1 and −2.0 ml min−1(1.73 m)−2for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was −29.5% (−44.8, −9.8;p p 1c(mmol/mol [95% CI]) at week 104 were similar between treatment groups: −6.84 (−7.64, −6.03), −7.74 (−8.54, −6.94) and −6.84 (−7.65, −6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c(% [95% CI]) at week 104 were: −0.63 (−0.70, −0.55), −0.71 (−0.78, −0.64) and −0.63 (−0.70, −0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively.Conclusions/interpretationErtugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1cdid not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria.Trial registrationclinicaltrials.govNCT01999218 and NCT02033889.

OBJECTIVE This study aimed to evaluate ertugliflozin in patients with overweight and obesity with type 2 diabetes mellitus. METHODS Data from three placebo-controlled, randomized, Phase 3 studies were pooled. Patients with baseline BMI ≥ 25 (1,377/1,544; 89%) were assessed with a stratification by BMI subgroup. RESULTS At week 26, reductions from baseline in glycated hemoglobin A1c (HbA1c), fasting plasma glucose, body weight (BW), and systolic blood pressure (SBP) were greater with ertugliflozin versus placebo. For placebo, ertugliflozin 5 mg, and ertugliflozin 15 mg, respectively, least squares mean change was 0.1%, -0.8%, and -0.9% for HbA1c and -1.2 kg, -3.1 kg, and -3.2 kg for BW. HbA1c reductions were consistent across BMI subgroups. For ertugliflozin 5 mg and 15 mg, least squares mean change (placebo adjusted) in absolute BW was -1.4 kg and -1.2 kg for BMI 25 to

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. https://ClinicalTrials.gov identifier: NCT01986855, NCT01999218, NCT01958671, NCT02099110, NCT02036515, NCT02033889, NCT02226003.

Objectives To evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use. Study Design We reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as “favorable” (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or “unfavorable’ (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively. Results We evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75–85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%–50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001). Conclusion Implant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.

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 Conclusion: Ertugliflozin demonstrated efficacy as monotherapy or with other antihyperglycaemic agents in patients with different demographic and disease characteristics and was generally well tolerated.

VERTIS CV was a placebo-controlled cardiovascular (CV) outcome trial evaluating the SGLT2 inhibitor ertugliflozin. The aim of current analyses was to examine pre-specified CV and kidney outcomes by Cox proportional hazard assessment according to use of renin-angiotensin-aldosterone system inhibitors (RAASi), diuretics, and mineralocorticoid receptor antagonists (MRA) at baseline. Among 8246 randomized patients, at baseline 6686 (81%) were treated with RAASi, 3542 (43%) with diuretics, including 1252 (15%) with loop diuretics, and 674 (8%) with MRA. No significant interactions were observed for cardiorenal outcomes by baseline use of RAASi or MRA (Pinteraction > 0.05 for all; FIGURE). Nominally significant interactions for first event of hospitalization for heart failure (HHF) and HHF/CV death were observed with baseline use of diuretics, including loop diuretics, with an increased benefit of ertugliflozin vs. placebo. In VERTIS CV, baseline use of diuretics, including loop diuretics, appeared to be associated with greater benefit of ertugliflozin on first HHF and HHF/CV death, with no modification of effect based on baseline use of RAASi or MRA. Disclosure D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. U. Masiukiewicz: Employee; Self; Pfizer Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. W. J. Shih: None. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None.

VERTIS CV was the cardiovascular (CV) outcome trial for the SGLT2 inhibitor ertugliflozin, conducted in patients with type 2 diabetes (T2D) and atherosclerotic CV disease. In the overall population, ertugliflozin was noninferior to placebo for major adverse CV events (MACE). Although superiority for the composite endpoint of CV death or hospitalization for heart failure (HHF) and the renal composite (that included doubling of serum creatinine from BL) were not met, the prespecified secondary objective of HHF showed a 30% risk reduction and a prespecified exploratory renal composite (sustained ≥40% decrease in eGFR from BL, dialysis/transplantation, or renal death) showed improved kidney outcomes. This analysis assessed cardiorenal endpoints of VERTIS CV by BL GLA. Among 8246 patients in VERTIS CV, at BL 6292 (76%) used metformin, 3900 (47%) insulin, 3390 (41%) sulfonylureas (SU), and 911 (11%) dipeptidyl peptidase-4 inhibitors (DPP4i), alone or in combination therapy (67% used >1 GLA at BL). For each of the GLAs, metformin, insulin, SU, and DPP4i, no significant differences were observed for cardiorenal outcomes by BL use (yes, no) of the GLA (FIGURE; all interaction P values >0.05). Cardiorenal outcomes were generally similar across the BL GLA subgroups. In VERTIS CV, the effects of ertugliflozin on cardiorenal outcomes in patients with T2D were generally consistent regardless of BL GLA. Disclosure B. Charbonnel: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly Diabetes, Merck & Co., Inc., Mundipharma International, Novo Nordisk, Sanofi, Speaker’s Bureau; Self; Takeda Pharmaceutical Company Limited. I. Gantz: Employee; Self; Merck & Co., Inc. R. Frederich: Employee; Self; Pfizer Inc., Other Relationship; Self; Merck Sharp & Dohme Corp., Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. J. P. Mancuso: Employee; Self; Pfizer Inc., Employee; Spouse/Partner; Pfizer Inc., Stock/Shareholder; Self; Pfizer Inc., Stock/Shareholder; Spouse/Partner; Pfizer Inc. R. E. Pratley: Other Relationship; Self; Hanmi Pharmaceutical, Merck Sharp & Dohme Corp., Metavention, Monster Energy Company, Inc., Novo Nordisk, Pfizer Inc., Poxel SA, Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. S. Dagogo-jack: Consultant; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Sanofi US, Stock/Shareholder; Self; Aerami Therapeutics, Jana Care Inc. C. P. Cannon: Advisory Panel; Self; Aegerion Pharmaceuticals Inc., Amarin Corporation plc, Corvidia Therapeutics, Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Pfizer Inc., Sanofi, Consultant; Self; Alnylam Pharmaceuticals, Inc., Amgen Inc., Applied Therapeutics, Ascendis Pharma A/S, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, HLS Therapeutics Inc., Kowa Company, Ltd., Research Support; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Daiichi Sankyo, Janssen Research & Development, LLC, Kowa Company, Ltd., Merck & Co., Inc., Novo Nordisk Pharma Ltd., Pfizer Inc. D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Scientific Affairs, LLC., Lilly Diabetes, Merck & Co., Inc., Mitsubishi-Tanabe, Maze Inc, Prometic, Novo Nordisk, Sanofi. F. Cosentino: Advisory Panel; Self; AstraZeneca, Merck Sharp & Dohme Corp., Pfizer Inc., Speaker’s Bureau; Self; Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Mundipharma International, Novo Nordisk. D. K. Mcguire: Consultant; Self; Applied Therapeutics, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., CSL Behring, Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Pfizer Inc., Sanofi. W. J. Shih: None. J. Liu: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Funding Merck Sharp & Dohme Corp

AIM To identify potential predictors and mediators of changes in β-cell function in response to ertugliflozin treatment in people with type 2 diabetes mellitus (T2DM). PARTICIPANTS AND METHODS Data from patients with T2DM randomized to ertugliflozin (5 or 15 mg; observations from both doses were pooled) or placebo in four phase 3 clinical studies (clinicaltrials.gov: NCT01958671, NCT02226003, NCT02036515, NCT02099110) were pooled and analysed. Change from baseline in β-cell function at week 26 was assessed, and its potential predictors and mediators were analysed using linear and multiple regression analyses. RESULTS Compared with placebo, ertugliflozin improved β-cell function when assessed by mean percent change from baseline in homeostatic model assessment of β-cell function (HOMA-%β; ertugliflozin: 14.7%, 95% confidence interval [CI] 12.3, 17.1; placebo: -0.4%, 95% CI -3.4, 2.5], but not when assessed by change in C-peptide index following a mixed meal tolerance test. Change in HOMA-%β correlated with change from baseline in glycated haemoglobin (HbA1c) and treatment with ertugliflozin, and weakly with change from baseline in body weight. In the ertugliflozin group, change in HOMA-%β correlated with baseline fasting plasma glucose (FPG; r = 0.235, P

To assess the efficacy and safety of once-weekly omarigliptin as monotherapy in people with type 2 diabetes mellitus (T2DM).People with T2DM not on glucose-lowering medications, or who were washed off monotherapy or low-dose dual therapy, were randomized double-blind to omarigliptin 25 mg (n=165) or matching omarigliptin placebo (n=164) for 24 weeks, followed by a 30-week period to assess continuing efficacy and safety longer-term of omarigliptin during which metformin was added to the placebo group and metformin placebo to the omarigliptin group.From a mean baseline HbA1c of 8.0-8.1%, the least squares mean (95% CI) change from baseline in HbA1c at week 24 (primary endpoint) was -0.49% (-0.73, -0.24) in the omarigliptin group and -0.10% (-0.34, 0.14) in the placebo group, for a between-group difference of -0.39% (-0.59, -0.19) (p.001). Protocol deviation in use of metformin by 38 of 252 (15%) people whose samples were available for evaluation probably attenuated glycemic efficacy results, as suggested by the LS mean difference -0.53% (-0.75, -0.32) after censoring of such participants. At 24 and 54 weeks, the incidences of adverse events (AEs) were similar in the omarigliptin and placebo groups. During 54 weeks there were no AEs of symptomatic hypoglycemia in the omarigliptin group and 5 AEs in the placebo group. Over 54 weeks, a majority of the omarigliptin treatment had a persistent reduction in HbA1c, remaining rescue-free.In people with T2DM, omarigliptin monotherapy improved glycemic control over 54 weeks and was generally well tolerated with a low risk of hypoglycemia. ClinicalTrials.gov Identifier: NCT01717313. EudraCT Number: 2012-003626-24.

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.

MK-0431-P083, a 54-week phase III study of the DPP-4 inhibitor sitagliptin as initial oral therapy in patients 10-17 years of age with T2D was initiated in 2012 and completed enrollment in 2018. After informed consent was obtained, patient screening was initiated with a screening visit (V1), followed by a single-blind, placebo run-in (V2) for 1 week, after which they were randomized (V3, N = 201). The changes observed in select laboratory and anthropometric parameters in these 201 patients between V1 and V3 (~25 days), and adverse events (AEs) reported during the 1-week placebo run-in (V2 to V3), were summarized in a preliminary analysis. Results: (mean ± SD [95% confidence interval]) are presented below. Between V1 and V3 (25 ± 7 days, median 23 days), A1C decreased from 7.72 ± 1.02% to 7.49 ± 1.03%, a change (Δ) of -0.23 ± 0.67% [-0.32, -0.13], while FPG was unchanged. Changes were also observed in ALT (Δ: -2.55 ± 11.21 IU [-4.15, -0.95]) and AST (Δ: -1.93 ± 9.08 IU [-3.22, -0.63]). Weight and lipid parameters were unchanged. Between V2 and V3, 75 AEs were reported for 40 patients (~20% of the randomized patients). Of these AEs, 3 were assessed to be drug-related by the investigators: 2 AEs of nervousness and dyspepsia in 1 patient, and an AE of worsening gastroesophageal reflux in another. None of the 75 AEs were assessed to be severe, and none led to discontinuation from the study. These data suggest that changes may be observed in glycemic parameters during a screening period of Disclosure C.A. Rosario: None. M.Y. Jalaludin: Advisory Panel; Self; Novo Nordisk Inc. Research Support; Self; Merck Sharp & Dohme Corp., Novo Nordisk Inc. R. Garcia: None. R.S. Newfield: Research Support; Self; Bristol-Myers Squibb Company, Daiichi Sankyo Company, Limited, Eli Lilly and Company, University of California and Rady Children's Hospital, San Diego. Y. Samoilova: None. N. Shehadeh: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. Speaker's Bureau; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. A. Pong: None. M. Zilli: Employee; Self; Merck Sharp & Dohme Corp. Stock/Shareholder; Self; Merck Sharp & Dohme Corp. C.K. Saha: Research Support; Self; Indiana University School of Medicine. S.S. Engel: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. P. Zeitler: Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Research & Development, Merck & Co., Inc., Novo Nordisk Inc. K.D. Kaufman: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. R. Shankar: Employee; Spouse/Partner; AstraZeneca. Employee; Self; Merck & Co., Inc. Employee; Spouse/Partner; NGM Biopharmaceuticals. Funding Merck & Co., Inc.

2 RCT evaluating ertugliflozin 5 mg (E5, n=652), 15 mg (E15, n=640) vs. non-ertugliflozin (NE, glimepiride or placebo, n=644) in T2D patients were pooled to evaluate effects on eGFR (MDRD) and albuminuria (UACR, geometric mean of % change from baseline). eGFR and UACR were analyzed by mixed model repeated measures with treatment, time, trial, baseline measures [A1C, SBP, eGFR/UACR] as covariates in overall population and by presence of UACR >30 mg/g. Baseline characteristics in the treatment groups were balanced. Overall, mean baseline eGFR was 88.2 ml/min/1.73m2 and geometric mean baseline UACR was 11.6 mg/g. At week 6, changes in eGFR were: -2.3, -2.7 and -0.7 ml/min/1.73m2, for the E5, E15 and NE groups, respectively. Mean eGFR with ertugliflozin increased over time, while it decreased in the NE group. The week 104 ΔeGFR [95% CI] compared to NE was 1.81 ([0.13, 3.49]; p=0.04) and 2.10 ml/min/1.73m2 ([0.42, 3.78]; p=0.01) for E5 and E15, respectively. In patients with baseline UACR > 30 mg/g (n=415) the ertugliflozin groups had greater UACR reductions. The week 104 ΔUACR [95% CI] compared to NE was -29.0% ([-47.0, -4.5]; p=0.02) for E5 and -32.7% ([-50.4, -8.6]; p=0.01) for E15. Ertugliflozin acutely reduced eGFR in an expected fashion, possibly based of known hemodynamic effects. Over 104 weeks, eGFR values were higher with ertugliflozin than control, suggestive of renal function preservation. Ertugliflozin reduced UACR in subjects with baseline albuminuria. Disclosure D. Cherney: Other Relationship; Self; AbbVie Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Prometic Life Sciences Inc., Sanofi. H.L. Heerspink: Consultant; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Fresenius Medical Care, Gilead Sciences, Inc., Janssen Research & Development, Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation. R. Frederich: Employee; Self; Pfizer Inc. Stock/Shareholder; Self; Bristol-Myers Squibb Company, Pfizer Inc. M. Maldonado: Employee; Self; Merck Sharp & Dohme Corp. A. Pong: None. Z. Xu: Employee; Self; Merck & Co., Inc. Stock/Shareholder; Self; Merck & Co., Inc. J. Liu: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. S.G. Terra: Employee; Self; Pfizer Inc. Funding Pfizer Inc.; Merck & Co., Inc.

Ertugliflozin (ERTU), a SGLT2 inhibitor, improves glycemic control in adults with T2DM. T2DM is prevalent among adults of Hispanic ethnicity in the U.S. Here we report a post hoc analysis of ERTU efficacy and safety in Hispanic/Latino pts in the ERTU Phase 3 program. A1C, body weight (BW), and systolic blood pressure (SBP) were evaluated with ERTU 5 and 15 mg (vs. placebo [PBO] or glimepiride [GLIM]) and ERTU with sitagliptin 100 mg (ERTU 5 or 15 mg/SITA vs. PBO or SITA). Adverse events (AEs) were evaluated. Among 4855 pts, baseline characteristics were generally similar across treatment groups and between the group of pts self-reported as Hispanic/Latino (n=1178, 24.3%) and the non-Hispanic/Latino group. No meaningful differences were observed between these ethnic groups in A1C reductions with ERTU 5 and 15 mg at week 26 in a pooled analysis of PBO-controlled studies, at week 52 in a GLIM-controlled study, or with ERTU 5 mg/SITA and ERTU 15 mg/SITA groups at week 26 in PBO- and SITA-controlled studies (Figure). Similarly, no meaningful differences between ethnic groups were observed in BW and SBP reductions with ERTU 5 and 15 mg across the program. ERTU was generally well tolerated. The incidence of AEs was similar between ethnic groups. ERTU efficacy and safety were similar between Hispanic/Latino and non-Hispanic/Latino groups. NCTs: 01958671, 02033889, 02036515, 01999218, 02226003, 02099110, 01986855. Disclosure J. Liu: Employee; Self; Merck & Co., Inc. L. Tarasenko: Employee; Self; Pfizer Inc. M.C. Ellison: Employee; Self; Merck & Co., Inc. A. Pong: None. S. Huyck: Employee; Self; Merck & Co., Inc. J.P. Mancuso: Employee; Self; Pfizer Inc. Employee; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Spouse/Partner; Pfizer Inc. Stock/Shareholder; Self; Pfizer Inc. S.G. Terra: Employee; Self; Pfizer Inc. I. Gantz: Employee; Self; Merck & Co., Inc. Funding Merck Sharp & Dohme Corp; Pfizer Inc.

BackgroundThe efficacy of ertugliflozin, a sodium–glucose cotransporter 2 inhibitor, for glycemic and blood pressure (BP) control has been demonstrated in phase 3 studies. To further evaluate the effects of ertugliflozin on BP and other hemodynamic parameters, an analysis was conducted on the pooled patient populations from these studies.MethodsThis was a post hoc analysis of data from three phase 3 studies (NCT01958671, NCT02033889, and NCT02036515) of adults with type 2 diabetes mellitus who received placebo, ertugliflozin 5 mg, or ertugliflozin 15 mg. Outcomes at 26 weeks were analyzed for the pooled population and according to relevant baseline factors, including BP.ResultsOf the 1544 patients included (placebo, n = 515; ertugliflozin 5 mg, n = 519; ertugliflozin 15 mg, n = 510), most (67.4–69.0%) had hypertension at baseline. Mean baseline BP was similar across treatment groups (placebo, 129.7/78.0 mmHg; ertugliflozin 5 mg, 131.0/78.4 mmHg; ertugliflozin 15 mg, 130.5/78.4 mmHg). At Week 26, placebo-adjusted least squares (LS) mean changes (95% confidence intervals [CI]) from baseline in systolic BP (SBP) were − 3.7 mmHg (− 5.1, − 2.3) for both ertugliflozin doses. Reductions were consistent across all baseline subgroups. At Week 26, more patients with a baseline SBP ≥ 130 mmHg had a SBP ConclusionErtugliflozin treatment led to reductions in SBP, DBP, and pulse rate relative to placebo. Reductions in SBP were generally consistent across the subgroups evaluated.Trial registrationNCT01958671; NCT02033889; NCT02036515

Ertugliflozin (ERTU) is a highly selective sodium-glucose cotransporter 2 inhibitor in development for treatment of patients with type 2 diabetes mellitus (T2DM). This pooled analysis characterized the efficacy and safety of ERTU when used as add-on therapy to metformin (MET). Pooled data from 2 randomized, double-blind, placebo-controlled Phase 3 studies with similar design and patient population (NCT02033889 [VERTIS MET], NCT02036515 [VERTIS SITA2]) were analyzed. Adult patients with T2DM inadequately controlled on MET (± sitagliptin) with A1C ≥7.0 to ≤10.5% were randomized to placebo (PBO), ERTU 5 mg or 15 mg for 26 weeks. Mean baseline (BL) characteristics of patients (N=1083) were similar across pooled treatment groups (age 57.7 years; T2DM duration 8.6 years; A1C 8.1%; body weight [BW] 85.7 kg; systolic blood pressure [SBP] 130.6 mmHg; estimated glomerular filtration rate 89.4 mL/min/1.73 m2). Changes in A1C, BW and SBP after 26 weeks are shown in the Table. Relative to PBO, more patients receiving ERTU had A1C Addition of ERTU to MET (± sitagliptin) provides reductions in A1C, BW and SBP, resulting in more patients achieving metabolic treatment goals.Table. Changes from baseline in A1C, BW and SBP at Week 26Placebo (n=362)Ertugliflozin 5 mg (n=363)Ertugliflozin 15 mg (n=358)Least squares mean change from baseline in A1C at Week 26 (95% CI), % Placebo-adjusted difference–0.1 (–0.2, 0.0) ––0.8 (–0.8, –0.7) –0.7 (–0.8, –0.6)–0.9 (–1.0, –0.8) –0.8 (–1.0, –0.7)Patients with A1C Disclosure R.A. Calle: Employee; Self; Pfizer Inc.. J. Liu: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. A. Pong: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..

Ertugliflozin (ERTU) is a sodium-glucose cotransporter 2 (SGLT2) inhibitor for the treatment of T2DM. Pharmacokinetic analysis indicates ERTU plasma exposure is not affected by race. The efficacy and safety of ERTU by race was assessed in pooled analyses from 3 randomized, double-blind, placebo (PBO)-controlled, Phase 3 trials. Patients received ERTU 5 mg, 15 mg or PBO for 26 weeks. Least-squares (LS) means for change from baseline to Week 26 were calculated for hemoglobin A1C (A1C), body weight (BW) and systolic blood pressure (SBP). General and prespecified adverse events (AEs) were evaluated. The analysis included 1544 patients (white 73%; black 7%; asian 15%; other 5%). Baseline demographics and characteristics were generally similar across treatment groups and racial groups, except lower mean BW and BMI in Asians. No notable differences in A1C, BW and SBP reductions were observed across racial groups (Table 1), except for a greater SBP reduction observed in Blacks. Across racial groups there were no notable differences in general AEs with ERTU vs. PBO. An increase in genital mycotic infections was seen with ERTU vs. PBO across all racial groups. Precision of between-treatment effects was limited in Blacks, Asians and Others due to small group size. ERTU efficacy and safety was generally similar across racial groups although a greater reduction in SBP was observed in Blacks.Table 1. Least-squares Mean Change (Placebo-corrected) in A1C, Body Weight and SBP from Baseline to Week 26 by Racial Group (Excluding Rescue Approach)RaceErtugliflozin Dose (N)*δA1C (%) LS mean (95% CI)δBody Weight (kg) LS mean (95% CI)δSBP (mmHg) LS mean (95% CI)Overall5 mg (519)-0.8 (-0.9, -0.7)-1.8 (-2.2, -1.4)-3.4 (-4.8, -2.0)15 mg (510)-0.9 (-1.0, -0.8)-1.8 (-2.2, -1.4)-3.5 (-4.9, -2.0)White5 mg (382)-0.8 (-1.0, -0.7)-1.9 (-2.3, -1.4)-3.3 (-4.9, -1.6)15 mg (374)-1.0 (-1.1, -0.8)-1.7 (-2.2, -1.2)-3.5 (-5.1, -1.8)Black5 mg (34)-0.7 (-1.2, -0.2)-1.1 (-2.8, 0.6)-9.5 (-16.0, -2.9)15 mg (37)-0.8 (-1.3, -0.3)-2.2 (-3.9, -0.6)-8.1 (-14.6, -1.7)Asian5 mg ( 77)-0.8 (-1.1, -0.5)-1.9 (-2.6, -1.1)-1.8 (-5.3, 1.8)15 mg (77)-1.0 (-1.3, -0.8)-2.1 (-2.8, -1.4)-1.9 (-5.4, 1.7)Other5 mg (26)-0.3 (-0.9, 0.3)-1.7 (-3.2, -0.2)-3.5 (-11.3, 4.4)15 mg (22)-0.9 (-1.5, -0.3)-1.5 (-3.0, 0.1)-4.4 (-12.8, 3.9)CI, confidence interval; LS, Least Squares *N is the number of randomized patients who took at least one dose of study medication. The LS Means for Change from Baseline to Week 26 were estimated from a constrained longitudinal data analysis model. Disclosure J. Liu: None. L. Tarasenko: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. A. Pong: None. S. Huyck: Employee; Self; Merck & Co., Inc.. L. Wu: None. J.P. Mancuso: Employee; Self; Pfizer Inc.. Stock/Shareholder; Self; Pfizer Inc.. Employee; Spouse/Partner; Pfizer Inc.. Stock/Shareholder; Spouse/Partner; Pfizer Inc. S. Terra: Employee; Self; Pfizer Inc. B. Lauring: Employee; Self; Merck & Co., Inc..

Background: This was a subgroup analysis of age group, dexamethasone use, and very highly emetogenic chemotherapy (VHEC) use from a randomised, multicentre, double-blind, Phase 3 study of oral aprepitant in paediatric subjects. Methods: Subjects aged 6 months to 17 years scheduled to receive chemotherapeutic agents associated with at least moderate risk for emesis were randomly assigned to receive either aprepitant plus ondansetron (aprepitant regimen) or placebo plus ondansetron (control regimen); both could be administered with or without dexamethasone. This secondary analysis evaluated subjects stratified by pre-specified age groups, dexamethasone use, and VHEC use. The primary endpoint of this analysis was the proportion of subjects who experienced complete response (CR) during the delayed phase. Results: CR rates in the delayed phase were numerically higher with the aprepitant than the control regimen across all age categories, and reached significance for subjects aged 12–17 years (51% vs. 10%; P

Ertugliflozin (ERTU), a sodium-glucose cotransporter 2 inhibitor, reduced glycated hemoglobin, body weight, and blood pressure (BP) in patients with type 2 diabetes mellitus (T2DM) in individual Phase 3 studies. This pooled analysis assessed effect on BP in a broader population and subgroups. A

In recent years, the modernization of traditional Chinese medicine (TCM) for treatment of patients with critical and life-threatening diseases has attracted much attention in the pharmaceutical industry. The modernization of TCM is based on a scientific evaluation of the safety and effectiveness of the TCM in terms of some well-established quantitative instruments. As a result, statistical validation of such an instrument is essential to have an accurate and reliable clinical assessment of the performance of the TCM. Similar to the validation of a typical quality of life instrument, some validation performance characteristics such as validity, reliability, and ruggedness are considered. In this article, a design for validation of a standard quantitative instrument that is commonly employed for diagnosis of a patient’s functions and activities, performance, signs and symptoms of disease, and disease status and severity based on Chinese diagnostic practice is proposed. Methods for statistical validation of the standard instrument are derived. A numerical example is given to illustrate the proposed methods for validation of Chinese diagnostic procedures.

In recentyears, the Westernization of traditional Chinese medicine (TCM) has attracted much attention in pharmaceutical research and development. One of the key issues in Westernization of TCM is how to conduct a scientifically valid clinical trial to evaluate safety and effectiveness of the TCM under investigation. A typical approach is to conduct a clinical trial the Western way by ignoring the fact that there are fundamental differences between a TCM and a West-em medicine intended for the same indication. These fundamental differences include (1) medical theory/mechanism and practice (ie, the concept of global dynamic balance/harmony among organs of the body versus local site of action); (2) techniques for diagnosis (ie, subjective diagnosis of inspection, auscultation and olfaction, interrogation, pulse taking and palpation versus objectively clinical evaluation); and (3) treatment (ie, personalized flexible dose of multiple components versus fixed dose). In this article, some practical issues, including validation of a quantitative instrument, the use of matching placebo, and sample size calculation when conducting a TCM clinical trial are discussed. We also discuss strategy for statistical quality control (QC) for raw materials, in-process materials or final product in terms of testing for consistency, stability analysis for estimation of drug expiration dating period, and regulatory requirements for future TCM research and development.

The sensation of pain arises from both central and peripheral sites, and inflammation may be one of its underlying causes. Combination therapy with analgesic agents having multimodal mechanisms of action and complementary pharmacokinetic properties enhances pain relief by addressing the different pathways of pain while limiting individual drug doses and, therefore, the potential for adverse effects caused by any single agent. Oxycodone and ibuprofen each have been used effectively as monotherapy and in other combinations for the treatment of acute pain; a fixed combination of these analgesics may improve pain relief in the setting of abdominal or pelvic surgery, where trauma and any resultant inflammation may be present at the same time.This study evaluated and compared the analgesic efficacy and tolerability of a single-dose combination tablet containing oxycodone 5 mg/ibuprofen 400 mg with either agent alone and with placebo in women who had undergone abdominal or pelvic surgery.In this multicenter, randomized, double-blind,placebo- and active-controlled, parallel-group trial, women experiencing moderate to severe pain between 14 and 48 hours after surgery were randomized per protocol to receive a single dose of study medication in a 3:3:1:1 ratio (combination oxycodone/ibuprofen, ibuprofen, oxycodone, and placebo, in that order). Over a 6-hour study period, patients recorded their assessments of pain intensity (100-mm visual analog scale and 4-point scale), relief from starting pain, and overall evaluation of study drug based on prespecified definitions and rating scales. Based on these data, the following primary efficacy end points were determined: total pain relief 6 hours after dosing (TOTPAR6) and sum of pain intensity differences 6 hours after dosing (SPID6). Other end points included the time to onset of pain relief, time to use of rescue medication, and patient's global rating of analgesic effectiveness. Tolerability was evaluated on the basis of observed and patient-reported adverse events and findings on physical examination.Four hundred fifty-six women participated in the study. They were primarily white and had a mean age of 41.6 years and a mean body weight of 171.5 pounds. Combination treatment was associated with significantly better TOTPAR6 and SPID6 scores compared with ibuprofen alone (P0.02 and P0.015, respectively), oxycodone alone (P0.009 and P0.001), or placebo (both, P0.001). Fewer patients receiving combination treatment required rescue medication, and the time to use of rescue medication was significantly longer in the combination-treatment group compared with the other groups (P0.05). Patients' global ratings of analgesic efficacy were significantly higher in the combination-treatment group compared with all other groups (P0.044 vs ibuprofen alone; P0.001 vs oxycodone alone and placebo). The onset of pain relief occurred within 15 minutes of dosing with all 4 regimens. Nausea was the most frequently reported treatment-emergent adverse event in all 4 groups. The incidence of treatment-emergent adverse events was highest with placebo (55.0%), followed by oxycodone alone (44.2%), ibuprofen alone (42.3%), and combination treatment (40.8%).In this population of women who had undergone abdominal or pelvic surgery, the combination of oxycodone 5 mg/ibuprofen 400 mg was significantly more effective than either agent alone or placebo in the treatment of moderate to severe postoperative pain.

e21685 Background: Chemotherapy-induced nausea and vomiting (CINV) is a distressing symptom of cancer treatment; in lung cancer, carboplatin is commonly used. In a post hoc analysis, we explored prevention of CINV in lung cancer patients with a single-day triple-antiemetic fosaprepitant (FA) regimen compared with a standard 3-day control regimen. Methods: This was a phase 3, global, randomized, double-blind, parallel-group study in adults scheduled to receive an intravenous (IV) dose of ≥1 moderately emetogenic chemotherapy (MEC) on treatment day 1 (NCT01594749). Subjects were randomly assigned 1:1 to a control or FA regimen. The control regimen consisted of 8 mg oral ondansetron, 20 mg dexamethasone, and IV saline as placebo before the first dose of MEC on day 1, and 8 mg oral ondansetron 8 hours after the first dose and every 12 hours on days 2 and 3. The FA regimen consisted of the same dose of oral ondansetron on day 1, along with 12 mg dexamethasone and a single dose of 150 mg IV FA before the first dose of MEC on day 1, with no additional prophylactic antiemetic beyond day 1. The primary end point was complete response (CR; no vomiting or rescue medication) in the delayed phase (25-120 hours). Results: Overall, 1000 subjects were included in the intention-to-treat population (FA: n = 502; control: n = 498). The primary end point was met ( P < 0.001; FA vs control). In a subset of 254 subjects with lung cancer (71% male), 129 in FA regimen and 125 in control regimen, most (98%) received carboplatin-based chemotherapy. CR in the delayed phase was achieved by 80.6% in the FA group and 74.4% in the control group (difference, 6.2%). More subjects had no vomiting episodes in the FA (85.3%) vs control (78.4%) groups within the delayed phase (difference, 6.9%), and overall time-to-first vomiting episode was longer for subjects in the FA group. Adverse events (AEs) were similar between groups: overall AEs occurred in 57.7% and 54.8%, and serious AEs occurred in 12.3% and 12.1% in the FA and control groups, respectively. No serious AEs were considered related to study medication. Conclusions: A single-day IV FA regimen is effective for preventing CINV in patients with lung cancer receiving carboplatin. Clinical trial information: NCT01594749.

In recent years, the concept of quality by design in (global) pharmaceutical development has received much attention. The purpose is to ensure that the compound under investigation will possess good drug characteristics such as identity, strength, purity, quality, safety, efficacy and stability before and post approval. A pharmaceutical development process consists of non-clinical (e.g., assay/process validation and stability testing), pre-clinical (e.g., animal and bioavailability/bioequivalence studies), and clinical (e.g., phases 1-3 clinical trials) development. In this article, various statistical designs that are commonly considered for achieving desired good drug characteristics as described in the United States Pharmacopeia and National Formulary (USP/NF) at various stages of non-clinical, pre-clinical, and clinical development are reviewed. In addition, the possible use of innovative adaptive clinical trial designs that may lead to (i) the identification of any signals, trends/patterns, and optimal clinical benefits of a test treatment under investigation, and (ii) increase the probability of success of the development process with limited resources available are discussed.

For approval of a drug product, the United States Food and Drug Administration (FDA) requires that substantial evidence of the effectiveness and safety of the drug product be provided through the conduct of two adequate, well-controlled clinical trials. To assist the sponsors in preparation of final clinical reports for regulatory submission and review, the FDA and other regulatory agencies and conferences such as the International Conference on Harmonization (ICH) have developed guidelines for the format and content of a clinical report. The FDA and ICH guidelines require that the following statistical issues be addressed in the final clinical report: I. Baseline comparability, 2. Adjustments for covariates, 3. Dropouts or missing values, 4. Interim analyses and data monitoring, 5. Multicenter studies, 6. Multiplicity, 7. Intention-to-treat subset versus efficacy subset, 8. Active control trials, and 9. Subgroup analyses. This paper provides an overview of these statistical issues. In addition, statistical justification for these issues is also addressed.

Vitamin D supplementation is recommended for women with osteoporosis. In the FOCUS-D trial comparing the combination tablet alendronate plus vitamin D3 5,600 IU (ALN/D) with standard care (SC) prescribed by patients’ personal physicians, ALN/D was more effective in improving serum 25(OH)D and bone turnover markers by 6 months and increasing spine and hip bone mineral density (BMD) after 1 year than SC. This post hoc analysis examined the relationship between BMD gain and 25(OH)D in women in SC receiving alendronate (SC/ALN, n = 134, 52 % of the SC group) and in the ALN/D group (n = 257). At baseline, participants were of mean age 73 years and 72 % were Caucasian, with a mean 25(OH)D of 14.9 ng/mL. In the SC/ALN group, most received vitamin D, although intake of vitamin D varied extensively (51 % received

In recent years, the use of adaptive methods in clinical development based on accrued data has become very popular due to its flexibility in modifying trial procedures and/or statistical procedures of on-going clinical trials. However, it is a concern that the actual patient population after the modifications could deviate from the originally targeted patient population. Major modifications of trial procedures and/or statistical procedures of on-going trials may result in a totally different trial, which is unable to address the scientific/medical questions that the trial intends to answer.

This open-label, multicenter study evaluated the efficacy, safety, and cycle control of Yasmin, a new low-dose, monophasic oral contraceptive containing the unique progestogen drospirenone (DRSP) 3 mg and ethinyl estradiol (EE) 30 microg. DRSP is a synthetic progestogen that has antiandrogenic and antimineralocorticoid effects. In this study, 326 women were evaluated and 220 (67%) completed all 13 treatment cycles. The corrected Pearl Index was 0. 407. Of the 151 subjects who experienced intermenstrual bleeding at any time during the study, the majority (64%) had bleeding during only one or two pill cycles. Breakthrough bleeding without spotting occurred in 1% of all cycles, spotting without breakthrough bleeding in 9.3% of all cycles, and breakthrough bleeding with spotting in 3% of all cycles. Amenorrhea was observed in 3% of all cycles. In all, 20 subjects (6%) discontinued participation in the study because of adverse events. No serious adverse events related to the study drug were reported. No clinically significant changes in weight, blood pressure, or lipids were reported. The impact of the new progestogen DRSP on the women's self-perception of menstrual health was also evaluated. Subjects reported that symptoms of water retention, negative affect, and increased appetite significantly improved at cycle 6 from baseline. This study demonstrates that Yasmin is an effective oral contraceptive that is safe and well tolerated.