James P. Mancuso

Recommendations for the Primary Analysis of Continuous Endpoints in Longitudinal Clinical Trials

This position paper summarizes relevant theory and current practice regarding the analysis of longitudinal clinical trials intended to support regulatory approval of medicinal products, and it reviews published research regarding methods for handling missing data. It is one strand of the PhRMA initiative to improve efficiency of late-stage clinical research and gives recommendations from a cross-industry team. We concentrate specifically on continuous response measures analyzed using a linear model, when the goal is to estimate and test treatment differences at a given time point. Traditionally, the primary analysis of such trials handled missing data by simple imputation using the last, or baseline, observation carried forward method (LOCF, BOCF) followed by analysis of (co)variance at the chosen time point. However, the general statistical and scientific community has moved away from these simple methods in favor of joint analysis of data from all time points based on a multivariate model (eg, of a mixed-effects type). One such newer method, a likelihood-based mixed-effects model repeated measures (MMRM) approach, has received considerable attention in the clinical trials literature. We discuss specific concerns raised by regulatory agencies with regard to MMRM and review published evidence comparing LOCF and MMRM in terms of validity, bias, power, and type I error. Our main conclusion is that the mixed model approach is more efficient and reliable as a method of primary analysis, and should be preferred to the inherently biased and statistically invalid simple imputation approaches. We also summarize other methods of handling missing data that are useful as sensitivity analyses for assessing the potential effect of data missing not at random.

Increased Food Intake and Energy Expenditure Following Administration of Olanzapine to Healthy Men

Atypical antipsychotic medications like olanzapine (OLZ) induce weight gain and increase the risk of diabetes in patients with schizophrenia. The goal of this study was to assess potential mechanisms of OLZ‐induced weight gain and accompanying metabolic effects. Healthy, lean, male volunteers received OLZ and placebo (PBO) in a randomized, double‐blind, crossover study. In periods 1 and 2, subjects received OLZ (5 mg for 3 days then OLZ 10 mg for 12 days) or matching PBO separated by a minimum 12‐day washout. Twenty‐four hour food intake (FI), resting energy expenditure (REE), activity level, metabolic markers, and insulin sensitivity (IS) were assessed. In total, 30 subjects were enrolled and 21 completed both periods. Mean age and BMI were 27 years (range: 18–49 years) and 22.6 ± 2.2 kg/m2, respectively. Relative to PBO, OLZ resulted in a 2.62 vs. 0.08 kg increase in body weight (P < 0.001) and 18% (P = 0.052 or 345 kcal) increase in FI. Excluding one subject with nausea and dizziness on the day of OLZ FI measurement, the increase in FI was 547 kcal, (P < 0.05). OLZ increased REE relative to PBO (113 kcal/day, P = 0.003). Significant increases in triglycerides, plasminogen activator inhibitor‐I (PAI‐I), leptin, and tumor necrosis factor‐α (TNF‐α) were observed. No significant differences in activity level or IS were observed. This study provides evidence that OLZ pharmacology drives the early increase in weight through increased FI, without evidence of decreased energy expenditure (EE), activity level, or short‐term perturbations in IS.

Blood Pressure Lowering Effects of a New Long-Acting Inhibitor of Phosphodiesterase 5 in Patients With Mild to Moderate Hypertension

Inhibition of phosphodiesterase 5 is an attractive candidate mechanism for blood pressure (BP) lowering. In this study, a novel long-acting phosphodiesterase 5 inhibitor, PF-00489791, was evaluated in 133 patients with mild to moderate hypertension, randomized into 1 of 4 groups: placebo, 4 mg, 10 mg, and 20 mg titrated after 14 days of dosing to 40 mg. Study medication was administered once daily for 28 days. Ambulatory BP monitoring was used. There was a statistically significant decrease (compared with placebo) in mean daytime systolic BP on day 28 at the 10 and 20/40 mg doses (by ≈5 and ≈7 mm Hg, respectively). Changes in mean daytime diastolic BP corresponded with those in systolic BP. The magnitude of BP lowering was greater on day 1 than on days 14 and 28, but the response was sustained between days 14 and 28. PF-00489791 also exerted BP lowering effects on mean 24-hour ambulatory BP. There was a dose-related increase in plasma cGMP concentration (statistically significant at the 20/40 mg dose). There was an increased incidence of headaches at the 10 and 20/40 mg doses (22% and 21%, respectively, compared with 12% with placebo) and an increased incidence of dyspepsia/gastroesophageal reflux disease and musculoskeletal adverse events at the 20/40 mg dose. In conclusion, PF-00489791 causes a clinically meaningful and sustained BP lowering in patients with hypertension. It is generally safe and well tolerated at the clinically efficacious doses.

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

To assess ertugliflozin in patients with type 2 diabetes who are inadequately controlled by metformin and sitagliptin.

Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: The VERTIS FACTORIAL randomized trial

To evaluate the efficacy and safety of ertugliflozin and sitagliptin co‐administration vs the individual agents in patients with type 2 diabetes who are inadequately controlled with metformin.

Ertugliflozin in Patients with Stage 3 Chronic Kidney Disease and Type 2 Diabetes Mellitus: The VERTIS RENAL Randomized Study

IntroductionErtugliflozin is a sodium-glucose cotransporter 2 inhibitor in development for type 2 diabetes mellitus (T2DM). The safety and efficacy of ertugliflozin were evaluated over 52xa0weeks in patients with chronic kidney disease (CKD).MethodsIn this double-blind randomized study (NCT01986855), patients with glycated hemoglobin (A1C) 7.0–10.5% and stage 3 CKD [estimated glomerular filtration rate (eGFR)xa0≥xa030 toxa0<xa060xa0mL/min/1.73xa0m2] who were undergoing treatment with standard diabetes therapy (or therapies) including insulin and/or sulfonylureas were randomized to once-daily ertugliflozin 5xa0mg, 15xa0mg, or placebo. Patients on metformin underwent a pre-randomizationxa0≥xa010-week wash-off period. The primary endpoint was change from baseline in A1C at weekxa026 in the overall cohort. Secondary efficacy endpoints were assessed in the stage 3A CKD cohort (eGFRxa0≥xa045 toxa0<xa060xa0mL/min/1.73xa0m2) at weeks 26 and 52. Safety was assessed in the overall cohort.Results468 patients were randomized (baseline mean A1C 8.2%). At week 26, reductions from baseline in A1C were observed across groups in the overall cohort [least squares mean changes (95% confidence interval) –xa00.3% (–xa00.4, –xa00.1), –xa00.3% (–xa00.4, –xa00.1), and –xa00.4% (–xa00.6, –xa00.3) for placebo and for ertugliflozin 5xa0mg and 15xa0mg, respectively]. Prohibited use of metformin was identified inxa0~xa017% of patients and impacted evaluation of the primary endpoint. Greater reductions from baseline in body weight, fasting plasma glucose, and systolic blood pressure were observed with ertugliflozin versus placebo at week 26 (stage 3A CKD cohort). The incidences of urinary tract infections, genital mycotic infections, and hypoglycemia adverse events were not meaningfully different between groups. The incidence of hypovolemia-related adverse events was higher with ertugliflozin relative to placebo.ConclusionAlthough surreptitious metformin use impacted the primary analysis, reductions in blood glucose and body weight were observed with ertugliflozin in patients with T2DM and stage 3 CKD; ertugliflozin had an acceptable safety profile.FundingMerck Sharp & Dohme Corp. a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Pfizer Inc.Trial RegistrationClinicaltrials.gov identifier NCT01986855.

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

IntroductionErtugliflozin 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.MethodsIn 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 5xa0mg once daily (QD) and sitagliptin 100xa0mg QD (E5/S100), ertugliflozin 15xa0mg QD and sitagliptin 100xa0mg QD (E15/S100), or placebo. The primary efficacy endpoint was the change from baseline in HbA1c at week 26.ResultsThe mean baseline HbA1c of the randomized patients (nxa0=xa0291) was 8.9%. At weekxa026, 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 −xa00.4% (−xa00.7, −xa00.2), −xa01.6% (−xa01.8, −xa01.4), and −xa01.7% (−xa01.9, −xa01.5) 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 HbA1cxa0<xa07.0%. 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.ConclusionCo-initiation of ertugliflozin with sitagliptin in patients with T2DM inadequately controlled on diet and exercise provided a clinically meaningful improvement in glycemic control over 26xa0weeks.Clinical Trial RegistrationClinicaltrials.gov NCT02226003.

Ertugliflozin Compared with Glimepiride in Patients with Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: The VERTIS SU Randomized Study

IntroductionThis study assessed the safety and efficacy of ertugliflozin (an oral sodium-glucose cotransporter 2 inhibitor) vs. glimepiride in patients with type 2 diabetes mellitus (T2DM) inadequately controlled on metformin.MethodsThis phase III, double-blind, non-inferiority study (NCT01999218) randomized patients with HbA1cxa0≥xa07.0% andxa0≤xa09.0% on stable metforminxa0≥xa01500xa0mg/day 1:1:1 to ertugliflozin 15 or 5xa0mg once-daily (QD), or glimepiride (titrated from 1xa0mg QD). The primary hypothesis was that ertugliflozin 15xa0mg was non-inferior to glimepiride on HbA1c (non-inferiority criterion: upper bound of the 95% confidence interval [CI] about the treatment differencexa0<xa00.3%).ResultsMean baseline HbA1c of randomized patients (Nxa0=xa01326) was 7.8%. Mean and median doses of glimepiride were 3.0xa0mg/day throughout the study. At week 52, the least squaresxa0mean change (95% CI) from baseline in HbA1c was −xa00.6% (−xa00.7, −xa00.5), −xa00.6% (−xa00.6, −xa00.5), and −xa00.7% (−xa00.8, −xa00.7) in the ertugliflozin 15xa0mg, ertugliflozin 5xa0mg, and glimepiride groups, respectively. The between-group difference for ertugliflozin 15xa0mg and glimepiride of 0.1% (−xa00.0, 0.2) met the pre-specified non-inferiority criterion. Relative to glimepiride, greater body weight and systolic blood pressure (SBP) reductions were observed with ertugliflozin. The overall incidence of adverse events (AEs) was similar across groups. The incidence of symptomatic hypoglycemia and genital mycotic infection (GMI) were, respectively, lower and higher with ertugliflozin relative to glimepiride. The incidences of urinary tract infection and hypovolemia AEs were not meaningfully different among the groups.ConclusionsErtugliflozin 15xa0mg was non-inferior to glimepiride in reducing HbA1c when added to metformin in patients with T2DM. Ertugliflozin had an acceptable safety profile and resulted in less hypoglycemia and more GMIs than glimepiride.Clinical Trial RegistrationClinicaltrials.gov NCT01999218.

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.