Estimating the effect of nintedanib on forced vital capacity in children and adolescents with fibrosing interstitial lung disease using a Bayesian dynamic borrowing approach.

BACKGROUND: The rarity of childhood interstitial lung disease (chILD) makes it challenging to conduct powered trials. In the InPedILD trial, among 39 children and adolescents with fibrosing ILD, there was a numerical benefit of nintedanib versus placebo on change in forced vital capacity (FVC) over 24 weeks (difference in mean change in FVC % predicted of 1.21 [95% confidence interval: -3.40, 5.81]). Nintedanib has shown a consistent effect on FVC across populations of adults with different diagnoses of fibrosing ILD. METHODS: In a Bayesian dynamic borrowing analysis, prespecified before data unblinding, we incorporated data on the effect of nintedanib in adults and the data from the InPedILD trial to estimate the effect of nintedanib on FVC in children and adolescents with fibrosing ILD. The data from adults were represented as a meta-analytic predictive (MAP) prior distribution with mean 1.69 (95% credible interval: 0.49, 3.08). The adult data were weighted according to expert judgment on their relevance to the efficacy of nintedanib in chILD, obtained in a formal elicitation exercise. RESULTS: Combined data from the MAP prior and InPedILD trial analyzed within the Bayesian framework resulted in a median difference between nintedanib and placebo in change in FVC % predicted at Week 24 of 1.63 (95% credible interval: -0.69, 3.40). The posterior probability for superiority of nintedanib versus placebo was 95.5%, reaching the predefined success criterion of at least 90%. CONCLUSION: These findings, together with the safety data from the InPedILD trial, support the use of nintedanib in children and adolescents with fibrosing ILDs.

A Physical Phantom for the Simulation of Neonatal Thermoregulation.

Preterm infants are at an increased health risk due to their low maturity. To monitor their health, vital signs are measured using contact-based methods. The adhesive sensors used to detect body temperature can damage the sensitive skin of neonates. Thus, a subject of current research is non-invasive measurement methods based on infrared thermography. In this context, thermal phantoms can be used to develop contactless temperature measurement systems and, furthermore, investigate the thermal behavior of preterm infants. In this work, an improved thermal phantom is introduced to simulate the thermoregulation of a premature infant. The shape and size are adapted to the body of a premature infant in the 29th week of pregnancy. The phantom consists of a 3D-printed frame to which carbon fiber heating elements and Pt1000 temperature sensors are attached. The frame is enclosed by a thermally conductive skin layer made of a silicone boron nitride mixture. Ball joints allow the body parts to tilt and rotate, enabling the phantom to model different body postures. Using PI controllers, the thermal phantom can achieve desired temperatures in 13 different areas of the body while maintaining a homogeneous temperature distribution on the skin surface. In addition, pathological temperature scenarios such as a central-peripheral temperature difference or a change in body temperature can be simulated with a maximum deviation of ± 0.4 °C.

Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD).

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD). METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial. ETHICS AND DISSEMINATION: The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical Practice and other local ethics committees. The study results will be disseminated at scientific congresses and in peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT05321082.

Decline in forced vital capacity as a surrogate for mortality in patients with pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Surrogate endpoints enable determination of meaningful treatment effects more efficiently than applying the endpoint of ultimate interest. We used data from trials of nintedanib in subjects with pulmonary fibrosis to assess decline in forced vital capacity (FVC) as a surrogate for mortality. METHODS: Data from the nintedanib and placebo groups of trials in subjects with idiopathic pulmonary fibrosis, other forms of progressive pulmonary fibrosis, and pulmonary fibrosis due to systemic sclerosis (NCT00514683, NCT01335464, NCT01335477, NCT01979952, NCT02999178, NCT02597933) were pooled. Using joint models for longitudinal and time-to-event data, we assessed the association between decline in FVC % predicted and time to death over 52 weeks. The rate of change in FVC % predicted and the current value of FVC % predicted were modelled longitudinally and estimates applied as predictors in time-to-event models. RESULTS: Among 2583 subjects with pulmonary fibrosis, both a greater rate of decline in FVC % predicted and a lower current value of FVC % predicted were associated with an increased risk of death over 52 weeks (HR 1.79 [95% CI: 1.57, 2.03] and HR 1.24 [1.17, 1.32] per 5-percentage point decrease, respectively). Associations between the rate of change in FVC % predicted and the risk of death were consistent between patients with IPF and other ILDs. CONCLUSION: Data from clinical trials in subjects with pulmonary fibrosis of diverse aetiology demonstrate a strong association between decline in FVC % predicted and mortality over 52 weeks, supporting FVC decline as a surrogate for mortality in these patients.

Multi-modal body part segmentation of infants using deep learning.

BACKGROUND: Monitoring the body temperature of premature infants is vital, as it allows optimal temperature control and may provide early warning signs for severe diseases such as sepsis. Thermography may be a non-contact and wireless alternative to state-of-the-art, cable-based methods. For monitoring use in clinical practice, automatic segmentation of the different body regions is necessary due to the movement of the infant. METHODS: This work presents and evaluates algorithms for automatic segmentation of infant body parts using deep learning methods. Based on a U-Net architecture, three neural networks were developed and compared. While the first two only used one imaging modality (visible light or thermography), the third applied a feature fusion of both. For training and evaluation, a dataset containing 600 visible light and 600 thermography images from 20 recordings of infants was created and manually labeled. In addition, we used transfer learning on publicly available datasets of adults in combination with data augmentation to improve the segmentation results. RESULTS: Individual optimization of the three deep learning models revealed that transfer learning and data augmentation improved segmentation regardless of the imaging modality. The fusion model achieved the best results during the final evaluation with a mean Intersection-over-Union (mIoU) of 0.85, closely followed by the RGB model. Only the thermography model achieved a lower accuracy (mIoU of 0.75). The results of the individual classes showed that all body parts were well-segmented, only the accuracy on the torso is inferior since the models struggle when only small areas of the skin are visible. CONCLUSION: The presented multi-modal neural networks represent a new approach to the problem of infant body segmentation with limited available data. Robust results were obtained by applying feature fusion, cross-modality transfer learning and classical augmentation strategies.

Plain language summary: Clinical study of BI 1015550 as a potential treatment for idiopathic pulmonary fibrosis.

WHAT IS THIS SUMMARY ABOUT?: This plain language summary describes the main findings from a trial in people with idiopathic pulmonary fibrosis (also called IPF) that was recently published in the New England Journal of Medicine. IPF is a rare disease, where the lungs become more and more scarred, with breathing and oxygen uptake becoming increasingly difficult. This trial looked at the medication BI 1015550 as a potential treatment for IPF. It compared BI 1015550 to placebo (a dummy drug that does not contain any active ingredients) to investigate the effectiveness of the drug in treating people with IPF. The study also looked at the additional medical issues (referred to as adverse events) reported during the study. Some participants took approved treatments to reduce scarring (nintedanib or pirfenidone), and some did not. WHAT WERE THE RESULTS?: Overall, 147 people with IPF from 22 countries took part in the trial. The results showed that BI 1015550 prevented lung function from decreasing in people with IPF. There was no difference in the percentage of patients with medical issues rated as severe by the study physician with BI 1015550 or placebo. However, more people treated with BI 1015550 had diarrhoea. Among those treated with BI 1015550, 13 participants stopped their treatment due to medical issues, whereas treatment was not stopped due to medical issues for any participants treated with placebo. WHAT DO THE RESULTS MEAN?: These results provide evidence that BI 1015550 prevents lung function from worsening in people with IPF. Further clinical studies will be conducted in the future to test BI 1015550 in a larger group of people with IPF and other forms of lung scarring that get worse over time, and for a longer time period.

Effect of Nintedanib on Progression of Systemic Sclerosis-Associated Interstitial Lung Disease Over 100 Weeks: Data From a Randomized Controlled Trial.

OBJECTIVE: In the SENSCIS trial, participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) were randomized to receive nintedanib or placebo until the last participant reached week 52 but for 100 weeks or less. Nintedanib reduced the rate of decline in forced vital capacity (FVC) (ml/year) over 52 weeks by 44% (41 ml [95% confidence interval (95% CI): 2.9-79.0]) versus placebo. We investigated the effect of nintedanib over the whole SENSCIS trial. METHODS: The annual rate of decline in FVC (ml/year) over the whole trial was assessed descriptively using 1) on-treatment data plus off-treatment data from participants who prematurely discontinued treatment (intent-to-treat analysis) and 2) only on-treatment data to assess the effect of nintedanib in participants who remained on treatment. RESULTS: In the intent-to-treat analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was -54.9 (11.1) and -88.8 (10.9) ml/year in the nintedanib (n = 287) and placebo (n = 288) groups, respectively (difference 34.0 ml/year [95% CI: 3.4-64.5]). In the on-treatment analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was -55.1 (12.3) and -94.0 (11.7) ml/year in the nintedanib (n = 286) and placebo (n = 288) groups, respectively (difference 38.9 ml/year [95% CI: 5.6-72.1]). The adverse event profile of nintedanib over 100 weeks was consistent with that observed over 52 weeks. CONCLUSION: Nintedanib provides a sustained benefit on slowing the progression of SSc-ILD over 100 weeks, with adverse events that are manageable for most patients.

Meta-Analysis of Effect of Nintedanib on Reducing FVC Decline Across Interstitial Lung Diseases.

INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations.

Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis.

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).

Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

A Setup for Camera-Based Detection of Simulated Pathological States Using a Neonatal Phantom.

Premature infants are among the most vulnerable patients in a hospital. Due to numerous complications associated with immaturity, a continuous monitoring of vital signs with a high sensitivity and accuracy is required. Today, wired sensors are attached to the patient's skin. However, adhesive electrodes can be potentially harmful as they can damage the very thin immature skin. Although unobtrusive monitoring systems using cameras show the potential to replace cable-based techniques, advanced image processing algorithms are data-driven and, therefore, need much data to be trained. Due to the low availability of public neonatal image data, a patient phantom could help to implement algorithms for the robust extraction of vital signs from video recordings. In this work, a camera-based system is presented and validated using a neonatal phantom, which enabled a simulation of common neonatal pathologies such as hypo-/hyperthermia and brady-/tachycardia. The implemented algorithm was able to continuously measure and analyze the heart rate via photoplethysmography imaging with a mean absolute error of 0.91 bpm, as well as the distribution of a neonate's skin temperature with a mean absolute error of less than 0.55 °C. For accurate measurements, a temperature gain offset correction on the registered image from two infrared thermography cameras was performed. A deep learning-based keypoint detector was applied for temperature mapping and guidance for the feature extraction. The presented setup successfully detected several levels of hypo- and hyperthermia, an increased central-peripheral temperature difference, tachycardia and bradycardia.

A Neonatal Phantom for Vital Signs Simulation.

Neonatal intensive care units provide vital medical support for premature infants. The key aspect in neonatal care is the continuous monitoring of vital signs measured using adhesive skin sensors. Since sensors can cause irritation of the skin and lead to infections, research focuses on contact-free, camera-based methods such as infrared thermography and photoplethysmography imaging. The development of image processing algorithms requires large datasets, but recording the necessary data from studies brings tremendous effort and costs. Therefore, realistic patient phantoms would be feasible to create a comprehensive dataset and validate image-based algorithms. This work describes the realization of a neonatal phantom which can simulate physiological vital parameters such as pulse rate and thermoregulation. It mimics the outer appearance of premature infants using a 3D printed base structure coated with several layers of modified, skin-colored silicone. A distribution of red and infrared LEDs in the scaffold enables the simulation of a PPG signal by mimicking pulsative light intensity changes on the skin. Additionally, the body temperature of the phantom is individually adjustable in several regions using heating elements. In the validation process for PPG simulation, the feasibility of setting different pulse frequencies and the variation of oxygen saturation levels was obtained. Furthermore, heating tests showed region-dependent temperature variations between 0.19 °C and 0.81 °C around the setpoint. In conclusion, the proposed neonatal phantom can be used to simulate a variety of vital parameters of preterm infants and, therefore, enables the implementation of image processing algorithms for the analysis of the medical state.

Survival analysis for AdVerse events with VarYing follow-up times (SAVVY)-estimation of adverse event risks.

BACKGROUND: The SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups. METHODS: Estimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment. RESULTS: Ten sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs. CONCLUSIONS: The choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly.

Study design of a randomised, placebo-controlled trial of nintedanib in children and adolescents with fibrosing interstitial lung disease.

Childhood interstitial lung disease (chILD) comprises >200 rare respiratory disorders, with no currently approved therapies and variable prognosis. Nintedanib reduces the rate of forced vital capacity (FVC) decline in adults with progressive fibrosing interstitial lung diseases (ILDs). We present the design of a multicentre, prospective, double-blind, randomised, placebo-controlled clinical trial of nintedanib in patients with fibrosing chILD (1199-0337 or InPedILD; ClinicalTrials.gov: NCT04093024). Male or female children and adolescents aged 6-17 years (≥30; including ≥20 adolescents aged 12-17 years) with clinically significant fibrosing ILD will be randomised 2:1 to receive oral nintedanib or placebo on top of standard of care for 24 weeks (double-blind), followed by variable-duration nintedanib (open-label). Nintedanib dosing will be based on body weight-dependent allometric scaling, with single-step dose reductions permitted to manage adverse events. Eligible patients will have evidence of fibrosis on high-resolution computed tomography (within 12 months of their first screening visit), FVC ≥25% predicted, and clinically significant disease (Fan score of ≥3 or evidence of clinical progression over time). Patients with underlying chronic liver disease, significant pulmonary arterial hypertension, cardiovascular disease, or increased bleeding risk are ineligible. The primary endpoints are pharmacokinetics and the proportion of patients with treatment-emergent adverse events at week 24. Secondary endpoints include change in FVC% predicted from baseline, Pediatric Quality of Life Questionnaire, oxygen saturation, and 6-min walk distance at weeks 24 and 52. Additional efficacy and safety endpoints will be collected to explore long-term effects.

The detailed clinical objectives approach to designing clinical trials and choosing estimands.

Objective setting is a necessary early step in the development of a clinical trial. ICH E9(R1) notes that the clinical objectives of a trial lead directly to the choice of estimands but barely discusses objectives themselves. Indeed, there is very little guidance anywhere in literature about objectives in clinical trials. This article identifies the substantial overlap between description of estimands and high quality definitions of objectives. It consequently shows that the estimand is decided by the precise choice of trial objective, and that therefore estimand decisions should be made at the objective level. The Detailed Clinical Objectives approach is proposed to support this. It emphasises clarity, specificity and a clinical focus when choosing and documenting objectives. Template text and examples are included to provide guidance on how it can be used in real trials. Finally, we describe objective-driven trial design, emphasising how strong objective setting establishes an important foundation for rigorous trial design discussions, logistical and operational decision-making during trial preparations, and clear communication of results and conclusions at the end of the trial. Highlighting the distinctions between objectives and estimands, we note how an objective-based framework can build on the ICH E9(R1) estimand framework to address many of its unanswered questions.

Composite endpoints in COPD: clinically important deterioration in the UPLIFT trial.

BACKGROUND: Assessments of lung function, exacerbations and health status are common measures of chronic obstructive pulmonary disease (COPD) progression and treatment response in clinical trials. We hypothesised that a composite endpoint could more holistically assess clinically important deterioration (CID) in a COPD clinical trial setting. METHODS: A composite endpoint was tested in a post hoc analysis of 5652 patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2-4 COPD from the 4-year UPLIFT study. Patients received tiotropium 18 µg or placebo. RESULTS: The composite endpoint included time to first confirmed decrease in trough forced expiratory volume in 1 s (FEV1) ≥100 mL, confirmed increase in St. George's Respiratory Questionnaire (SGRQ) total score ≥ 4 units, or moderate/severe exacerbation. Most patients (> 80%) experienced CID, with similar incidence among GOLD subgroups. Most confirmed trough FEV1 (74.6-81.6%) and SGRQ (72.3-78.1%) deteriorations were sustained across the study and in all GOLD subgroups. Patients with CID more frequently experienced subsequent exacerbation (hazard ratio [HR] 1.79; 95% confidence interval [CI] 1.67, 1.92) or death (HR 1.21; 95% CI 1.06, 1.39) by Month 6. CID was responsive to bronchodilator treatment. CONCLUSIONS: Composite endpoints provide additional information on COPD progression and treatment effects in clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00144339 .

Health-related Quality of Life in the Phase III LUME-Colon 1 Study: Comparison and Interpretation of Results From EORTC QLQ-C30 Analyses.

INTRODUCTION: We used European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) data from the LUME-Colon 1 study to illustrate different methods of statistical analysis for health-related quality of life (HRQoL), and compared the results. PATIENTS AND METHODS: Patients were randomized 1:1 to receive nintedanib 200 mg twice daily plus best supportive care (n = 386) or matched placebo plus best supportive care (n = 382). Five methods (mean treatment difference averaged over time, using a mixed-effects growth curve model; mixed-effects models for repeated measurements (MMRM); time-to-deterioration (TTD); status change; and responder analysis) were used to analyze EORTC QLQ-C30 global health status (GHS)/QoL and scores from functional scales. RESULTS: Overall, GHS/QoL and physical functioning deteriorated over time. Mean treatment difference slightly favored nintedanib over placebo for physical functioning (adjusted mean, 2.66; 95% confidence interval [CI], 0.97-4.34) and social functioning (adjusted mean, 2.62; 95% CI, 0.66-4.47). GHS/QoL was numerically better with nintedanib versus placebo (adjusted mean, 1.61; 95% CI, -0.004 to 3.27). MMRM analysis had similar results, with better physical functioning in the nintedanib group at all timepoints. There was no significant delay in GHS/QoL deterioration (10%) and physical functioning (16%) with nintedanib versus placebo (TTD analysis). Status change analysis showed a higher proportion of patients with markedly improved GHS/QoL and physical functioning in the nintedanib versus placebo groups. Responder analysis showed a similar, less pronounced pattern. CONCLUSION: Analyses of EORTC QLQ-C30 data showed that HRQoL was not impaired by treatment with nintedanib versus placebo. Analysis and interpretation of HRQoL endpoints should consider symptom type and severity and course of disease.

Dose Determination for a Fixed-Dose Drug Combination: A Phase II Randomized Controlled Trial for Tiotropium/Olodaterol Versus Tiotropium in Patients with COPD.

INTRODUCTION: During the clinical development of a fixed-dose combination of drugs, it is best practice to conduct dose-finding studies to determine the optimal dose of each component. The aims of this phase II dose-finding study were to confirm the lung function benefit of adding olodaterol to tiotropium, describe the dose-response relationship of olodaterol in combination with tiotropium 5 µg, and compare it with the dose response of olodaterol monotherapy. METHODS: In this double-blind, parallel-group trial, patients were randomized to receive either tiotropium 5 µg or a fixed-dose combination of tiotropium 5 µg with olodaterol 2 µg, 5 µg, or 10 µg, delivered once daily via the Respimat® for 4 weeks (NCT00696020). Patients had a diagnosis of chronic obstructive pulmonary disease and post-bronchodilator forced expiratory volume in 1 s (FEV1) ≥ 30 and < 80% of predicted normal. The primary endpoint was trough FEV1 response (change from baseline) after 4 weeks. Secondary endpoints included FEV1 and forced vital capacity (FVC) over 6 h after dosing. RESULTS: Compared with tiotropium 5 µg, mean (standard error) trough FEV1 increased with the addition of olodaterol 2 µg by 0.024 L (0.027), olodaterol 5 µg by 0.033 L (0.027), and olodaterol 10 µg by 0.057 L (0.027). Statistically significant improvements in FEV1 versus tiotropium were seen across all timepoints up to 6 h with all doses of tiotropium/olodaterol. Similar results were observed for FVC. CONCLUSION: There was a benefit of tiotropium/olodaterol compared with tiotropium monotherapy in FEV1 and FVC. There was a dose-response relationship for olodaterol on top of tiotropium for FEV1 and FVC similar to the dose response previously seen for olodaterol monotherapy. These results, together with the results of a study investigating the dose response of tiotropium on top of olodaterol, helped to inform the dose selection for the phase III studies. FUNDING: Boehringer Ingelheim International GmbH.

Effects of baseline symptom burden on treatment response in COPD.

RATIONALE: In symptomatic patients with COPD, the decision whether to initiate maintenance treatment with a single agent or a combination of long-acting bronchodilators remains unclear. OBJECTIVE: To investigate whether baseline symptomatic status influences response to tiotropium/olodaterol treatment. MATERIALS AND METHODS: Post hoc analysis of the randomized OTEMTO® studies (NCT01964352; NCT02006732), in which patients with moderate-to-severe COPD received placebo, tiotropium 5 µg, tiotropium/olodaterol 2.5/5 µg, or tiotropium/olodaterol 5/5 µg once daily for 12 weeks via the Respimat® inhaler (Boehringer Ingelheim, Ingelheim am Rhein, Germany). Impact of baseline symptomatic status (modified Medical Research Council [mMRC] score) on response to treatment with tiotropium/olodaterol 5/5 µg, tiotropium 5 µg, or placebo at Week 12 was assessed by St George's Respiratory Questionnaire (SGRQ) total score and response rate, transition dyspnea index (TDI) focal score and response rate, and trough forced expiratory volume in 1 second response. RESULTS: Tiotropium/olodaterol improved SGRQ total scores and response rates compared with placebo and tiotropium for patients with baseline mMRC scores 0-1 and ≥2. For tiotropium/olodaterol vs tiotropium, greater improvements were observed for patients with mMRC ≥2 (SGRQ score adjusted mean treatment difference -3.44 [95% CI: -5.43, -1.46]; P=0.0007; SGRQ response rate ORs 2.09 [95% CI: 1.41, 3.10]; P=0.0002). Dyspnea, measured by TDI score, was consistently improved with tiotropium/olodaterol vs placebo for patients with mMRC scores 0-1 and ≥2 (adjusted mean treatment difference 1.63 [95% CI: 1.06, 2.20]; P<0.0001 and 1.60 [95% CI: 1.09, 2.10]; P<0.0001, respectively). In patients with mMRC scores 0-1 and ≥2, tiotropium/olodaterol consistently improved TDI response rate and lung function vs placebo and tiotropium. CONCLUSIONS: Patients with COPD with more severe baseline dyspnea appear to derive greater health status benefit with tiotropium/olodaterol compared with tiotropium alone.