Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study.

AIMS/HYPOTHESIS: Type 2 diabetes, particularly with concomitant CVD, is associated with an increased risk of cognitive impairment. We assessed the effect on accelerated cognitive decline (ACD) of the DPP-4 inhibitor linagliptin vs the sulfonylurea glimepiride in individuals with type 2 diabetes. METHODS: The CAROLINA-COGNITION study was part of the randomised, double-blind, active-controlled CAROLINA trial that evaluated the cardiovascular safety of linagliptin vs glimepiride in individuals with age ≥40 and ≤85 years and HbA1c 48-69 mmol/mol (6.5-8.5%) receiving standard care, excluding insulin therapy. Participants were randomised 1:1 using an interactive telephone- and web-based system and treatment assignment was determined by a computer-generated random sequence with stratification by center. The primary cognitive outcome was occurrence of ACD at end of follow-up, defined as a regression-based index score ≤16th percentile on either the Mini-Mental State Examination (MMSE) or a composite measure of attention and executive functioning, in participants with a baseline MMSE score ≥24. Prespecified additional analyses included effects on ACD at week 160, in subgroups (sex, age, race, ethnicity, depressive symptoms, cardiovascular risk, duration of type 2 diabetes, albuminuria), and absolute changes in cognitive performance. Participants, caregivers, and people involved in measurements, examinations or adjudication, were all masked to treatment assignment. RESULTS: Of 6033 participants recruited from hospital and primary care sites, 3163 (38.0% female, mean age/diabetes duration 64/7.6 years, MMSE score 28.5, HbA1c 54 mmol/mol [7.1%]) represent the CAROLINA-COGNITION cohort. Over median 6.1 years, ACD occurred in 27.8% (449/1618, linagliptin) vs 27.6% (426/1545, glimepiride), OR 1.01 (95% CI 0.86, 1.18). Also, no differences in ACD were observed at week 160 (OR 1.07 [0.91, 1.25]), between treatments across subgroups, or for absolute cognitive changes. CONCLUSIONS/INTERPRETATION: In a large, international outcome trial in people with relatively early type 2 diabetes at elevated cardiovascular risk, no difference in risk for ACD was observed between linagliptin and glimepiride over 6.1 years. FUNDING: This study was sponsored by Boehringer Ingelheim. TRIAL REGISTRATION: ClinicalTrials.gov NCT01243424.

What is an estimand & how does it relate to quantifying the effect of treatment on patient-reported quality of life outcomes in clinical trials?

BACKGROUND: Published in 2019, a new addendum to the ICH E9 guideline presents the estimand framework as a systematic approach to ensure alignment among clinical trial objectives, trial execution/conduct, statistical analyses, and interpretation of results. The use of the estimand framework for describing clinical trial objectives has yet to be extensively considered in the context of patient-reported outcomes (PROs). We discuss the application of the estimand framework to PRO objectives when designing clinical trials in the future, with a focus on PRO outcomes in oncology trial settings as our example. MAIN: We describe the components of an estimand and take a naïve PRO trial objective to illustrate how to apply attributes described in the estimand framework to inform construction of a detailed clinical trial objective and its related estimand. We discuss identifying potential post-randomization events that alter the interpretation of the endpoint or render its observation impossible (also defined as intercurrent events) in the context of PRO endpoints, and the implications of how to handle intercurrent events in the construction of the PRO objective. Using a simple objective statement, "What is the effect of treatment X on patient's quality of life?", we build up an example estimand statement and also use a previously published phase III oncology clinical trial to illustrate how an estimand for a PRO objective could have been written to align to the estimate framework. CONCLUSION: The use of the estimand framework, as described in the new ICH E9 (R1) addendum guideline will become a key common framework for developing clinical trial objectives for evaluating effects of treatment. In the context of considering PROs, the framework provides an opportunity to more precisely specify and build the rationale for patient-focused objectives. This will help to ensure that clinical trials used for registration are designed and analysed appropriately, enabling all stakeholders to accurately interpret conclusions about the treatment effects for patient-focused outcomes.

Strategic and Statistical Considerations on the QT Assessment of Volasertib.

Volasertib is a selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). A potential for prolonged QT intervals was indicated with volasertib in preclinical studies and preliminary clinical data. As a result, electrocardiograms (ECGs) have been collected in all volasertib clinical trials to monitor potential cardiac effects. This article describes strategic and statistical methods prospectively planned to perform an integrated analysis of ECG data from available trials to evaluate volasertib's effect on cardiac repolarization, as reflected by changes in the duration of QT interval and other ECG-related endpoints. Methods to effectively cope with heterogeneity between trials (ie, differences in study designs) are discussed. These strategies may be useful for other investigational drugs for which QT risk assessment is required, but a thorough QT/QTc trial is not feasible, resulting in the need for an alternative approach. Volasertib therapy relevantly prolonged adjusted mean QTcF change from administration baseline following the first and subsequent infusions. The integrated analysis revealed that the volasertib effects on the mean QTc changes from baseline were transient and had resolved at 24 hours after start of the first infusion. There was no evidence for a long-term impact on the QTcF interval following multiple infusions with volasertib.

Efficacy and Safety Results of the Afatinib Expanded Access Program.

INTRODUCTION: Afatinib is an oral, irreversible ErbB family blocker approved for first-line treatment of metastatic epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). The expanded access program (EAP) allowed early access to afatinib and provided additional data on its safety, tolerability, and efficacy. METHODS: The afatinib EAP was an open-label, multicenter, single-arm program in the United States that treated and followed patients with locally advanced or metastatic NSCLC harboring EGFR mutations. Afatinib 40 mg was administered orally once daily until discontinuation due to disease progression, adverse events (AEs), or transition to commercially available drug. RESULTS: Three hundred twenty-two patients received ≥1 dose of afatinib. Most patients had received prior therapies. Drug-related AEs occurred in 89.4% of patients, including 7.8% with serious AEs. The most common afatinib-related AEs (all grades) were diarrhea (77.0%) and rash (36.0%). Dose reductions occurred in 31.1% of patients. Discontinuation rates due to diarrhea (1.6%) or rash/acne (0.3%) were low. Efficacy data were collected and analyzed when available, with 17.1% and 69.9% of patients achieving objective response and disease control, respectively, in this highly pretreated population. CONCLUSIONS: No additional or unexpected safety concerns were revealed, and afatinib demonstrated antitumor activity in a heavily pretreated NSCLC patient population in a routine clinical setting. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01649284. FUNDING: Boehringer Ingelheim Pharmaceuticals, Inc.

Influence of Renal Impairment on the Pharmacokinetics of Afatinib: An Open-Label, Single-Dose Study.

BACKGROUND AND OBJECTIVE: Afatinib is an oral irreversible ErbB-Family Blocker indicated for treatment of patients with EGFR mutation positive advanced non-small cell lung cancer. This trial assessed whether renal impairment influences the pharmacokinetics and safety of afatinib. METHODS: This was an open-label, single-dose study. Pharmacokinetic parameters after afatinib 40 mg were investigated in subjects with moderate (n = 8) or severe (n = 8) renal impairment (estimated glomerular filtration rate 30-59 mL/min/1.73 m2 and 15-29 mL/min/1.73 m2, respectively) and healthy matched controls (n = 14). Plasma and urine samples were collected before and up to 14 days after dosing for pharmacokinetic and plasma protein-binding assessment. Primary endpoints were area under the plasma concentration-time curve from time zero to the last quantifiable concentration (AUClast) and maximum plasma concentration (C max) between subjects with renal impairment and healthy matched controls. RESULTS: Pharmacokinetic profiles and plasma protein binding were similar in all groups. The extent of exposure, as indicated by AUClast and C max, was generally similar between the matched treatment groups, with the exception of the geometric mean ratio of AUClast for subjects with severe renal impairment, which showed a trend towards a higher value compared with matched healthy subjects (150.0 % [90 % CI 105.3-213.7]) Inter-individual variability was moderate (geometric mean coefficient of variation 28-39 % for moderate impairment, 34-42 % for severe impairment). Afatinib was well tolerated and urinary excretion was minimal. CONCLUSION: Moderate-to-severe renal impairment had a minor influence on the pharmacokinetics of afatinib that was within the observed inter-individual variability, suggesting that afatinib treatment can be considered in this patient population. Registered at ClinicalTrials.gov as NCT02096718.

Phase II, open-label trial to assess QTcF effects, pharmacokinetics and antitumor activity of afatinib in patients with relapsed or refractory solid tumors.

PURPOSE: Afatinib is an irreversible ErbB family blocker currently under evaluation in late-stage clinical trials. This study primarily assessed the cardiac safety, pharmacokinetics and antitumor activity of afatinib in cancer patients. METHODS: In this multicenter, Phase II, open-label, single-arm trial, 60 patients with solid tumors who were expected to express epidermal growth factor receptor-1 and HER2 received oral afatinib 50 mg daily. QTcF intervals (QT interval corrected by the Fridericia formula) were evaluated based on electrocardiogram recordings time-matched with pharmacokinetic blood samples after single (Day 1) and continuous (Day 14; steady state) administration. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), version 3.0; antitumor activity was assessed using RECIST 1.0. RESULTS: There was a nonsignificant decrease of 0.3 ms (90 % confidence interval -2.8, 2.3; N = 49) in the mean of the average time-matched QTcF interval from baseline to steady state. The maximum plasma concentration for afatinib was seen at median tmax 3 h after both single dose and at steady state. No relationship between afatinib plasma concentrations and time-matched QTcF, QT and heart rate change was found. The overall adverse event profile was consistent with the known safety profile of afatinib. One patient demonstrated a partial response (PR) and two patients unconfirmed PRs. CONCLUSIONS: Afatinib had no impact on cardiac repolarization, had a manageable safety profile and demonstrated antitumor activity in this uncontrolled study.

Effect of small angiokinase inhibitor nintedanib (BIBF 1120) on QT interval in patients with previously untreated, advanced renal cell cancer in an open-label, phase II study.

PURPOSE: Some targeted anticancer agents are associated with serious ventricular tachyarrhythmias, which may be predicted by electrocardiographic evaluation of drug-related QT prolongation. We studied the effects of nintedanib (BIBF 1120; an oral, triple angiokinase inhibitor targeting vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors) on the QT interval in patients with renal cell carcinoma (RCC) participating in an open-label phase II trial. METHODS: Treatment-naïve, adult patients with unresectable/metastatic, clear cell RCC received nintedanib 200 mg twice daily. QT intervals were evaluated at baseline (day -1), on day 1 (after the first dose), and on day 15 (steady state) by 12-lead electrocardiograms (ECGs) performed in triplicate. Pharmacokinetic sampling was also undertaken. RESULTS: Among 64 evaluable patients, the upper limits of the 2-sided 90 % confidence intervals for the adjusted mean time-matched changes in QTcF interval (corrected for heart rate by Fridericia's method) from baseline to day 1 and 15 (primary ECG endpoint) were well below the regulatory threshold of 10 ms at all times. No relationship between nintedanib exposure and change from baseline in QTcF was seen. Nintedanib was generally well tolerated with no drug-related cardiovascular adverse events. CONCLUSION: Nintedanib administered at 200 mg twice daily was not associated with clinically relevant QT prolongation.

Pharmacokinetics and tolerability (Study 1) with particular reference to ocular safety (Study 2) of tiotropium Respimat soft mist inhaler: findings from two dose-ranging studies in healthy men.

Data are presented from two randomized, double-blind, placebo-controlled studies in which the tolerability of tiotropium Respimat Soft MistTM Inhaler (SMI), a new-generation, propellant-free device for use in COPD, and the ocular safety oftiotropium were examined. In Study 1, 36 healthy males received tiotropium 8, 16, or 32 microg (n = 9/dose) or placebo (n = 3/dose level), administered once daily via Respimat SMI for 14 days. Safety and pharmacokinetics were evaluated. In Study 2, 48 healthy males received tiotropium 0.02, 0.04, 0.08, 0.16, 0.28, or 0.40 microg (n = 6/dose) or placebo (n = 2/dose level), applied as two drops to one eye (the highest dose was a significant multiple of a percentage of the proposed Respimat SMI clinical dose that could be inadvertently deposited in the eye). Ocular parameters were measured over 24 hours. Tiotropium Respimat SMI at doses up to 32 microg was well tolerated in Study 1; typical dose-dependent anticholinergic adverse events of mild-to-moderate intensity were observed. In Study 2, ocular tiotropium administration did not affect pupil diameter, pupillary reflex, intraocular pressure, or accommodation. Tiotropium Respimat SMI was well tolerated. Inadvertent ocular exposure to tiotropium up to 0.40 g is unlikely to result in ocular adverse effects.

Lung deposition of radiolabeled tiotropium in healthy subjects and patients with chronic obstructive pulmonary disease.

Lung deposition of 18 microg tiotropium administered via a dry-powder inhaler was investigated in 5 healthy subjects and patients with mild (n = 4), moderate (n = 6), and severe (n = 5) chronic obstructive pulmonary disease after 14 days of treatment with 18 microg tiotropium. On day 15, subjects inhaled 2 capsules of radiolabeled tiotropium, and lung deposition was assessed using gamma scintigraphy. Repeated plasma and urine collections were performed on days 14 and 15. Mean delivered dose from the dry-powder inhaler was 45.1%. Mean lung deposition relative to the delivered dose was 42% (19%, relative to nominal dose) with low intersubject variability (20%). Mean extrathoracic deposition was 57.5% (25.8%, relative to nominal dose). There were no significant differences in deposition among the subgroups. No significant correlation between individual tiotropium deposition and lung function was observed. These results suggest that all stages of chronic obstructive pulmonary disease may gain full therapeutic benefit from the drug.

Meloxicam does not affect the antiplatelet effect of aspirin in healthy male and female volunteers.

This study determined if meloxicam, a selective cyclooxygenase (COX)-2 inhibitor, interferes with the antiplatelet effect of aspirin using platelet aggregation and thromboxane (Tx) B(2) endpoints in healthy volunteers. Eight male and 8 female volunteers participated in this open-label, randomized, two-treatment, two-way crossover trial. Treatment 1 was meloxicam (15 mg qd) over 4 days, and then aspirin (100 mg qd) was ingested 2 hours after meloxicam for an additional 7 days. Blood samples were taken 2, 6, and 24 hours after the last dose. Treatment 2 consisted of only aspirin (100 mg) over 2 days. Samples were taken at the same time points. Each subject received both treatments with a 2-week washout between the treatment periods. Treatments were safe and well tolerated. The initial 4-day treatment with meloxicam had no effect on platelet aggregation but reduced serum TxB(2) by 64% +/- 19%. Addition of aspirin (100 mg qd) for 7 days resulted in complete inhibition of aggregation and TxB(2) for 24 hours. Two-day treatment with only 100 mg aspirin also resulted in complete inhibition of platelet aggregation and TxB(2). These results indicate that meloxicam does not affect the ability of aspirin to inhibit COX-1 in platelets, thereby allowing aspirin to effectively prevent platelet aggregation and reduce TxB(2) levels, and that meloxicam is selective for COX-2.