Flexible Designs in klinischen Prüfungen mit binärer und ordinaler Zielvariable

In dieser Arbeit werden klinische Studien mit flexiblem Design untersucht. Hierbei handelt es sich um in mehreren voneinander unabhängigen Stufenabschnitten durchgeführten Verfahren, die basierend auf den bis zu einem bestimmten Zeitpunkt vorliegenden Information Änderungen am Studiendesign erlauben. Zur Kombination der Ergebnisse der einzelnen Sequenzen werden die gewichtete inverse Normal- sowie die verallgemeinerte inverse x^2-Methode betrachtet (vgl. Hartung (2006)). Wird die Anzahl der Sequenzen fest vorgegeben, handelt es sich um adaptiv gruppensequentielle Verfahren. Diese ermöglichen neben der Anpassung des Studiendesigns eine Überprüfung des Testproblems in jeder Zwischenauswertung. Die durch das mehrfache Testen resultierende Erhöhung des Fehlers I. Art erfordert eine Adjustierung der kritischen Schranken. Hierfür werden die Strategien von Pocock (1977), O'Brien und Fleming (1979), Wang und Tsiatis (1987) sowie Haybittle (1971) und Peto et al. (1976) vorgestellt. Die beiden letzteren werden für die Kombination der Ergebnisse mit der inversen x^2-Methode übertragen. Die zugehörigen kritische Werte, welche mittels Simulationen erhalten wurden, werden angegeben. Kommt das Self-Designing klinischer Studien zur Anwendung, ist die Anzahl der Sequenzen zu Beginn der Untersuchung offen. Zudem wird die Gewichtung der einzelnen Stufen basierend auf den vorliegenden Beobachtungen bestimmt. Bei Verwendung der inversen x^2-{Methode kann in jeder Sequenz die Überprüfung der Nullhypothese erfolgen, bei der inversen Normalmethode hingegen erst nach Vergabe des globalen Gewichts. Neben der Überprüfung von Testproblemen ist die Abschätzung des Ausma es eines Wirkungsunterschieds von Interesse. Hierfür werden für die verschiedenen Designs geeignete Methoden für die Punkt- und Intervallschätzung vorgestellt. Für den Fall, dass in den Zwischenauswertungen kein Testen der Nullhypothese sondern nur eine Anpassung der Fallzahl erfolgt, wird ein unverzerrter Schätzer hergeleitet. Die in der Literatur vorgestellten flexiblen Designs basieren häufig auf der Annahme normalverteilter Zielvariable mit bekannter Varianz. Für die Untersuchung dieser Designs bei Vorliegen diskreter Beobachtungen werden klinische Studien mit binärer und ordinaler Zielgröße betrachtet. Für beide Fälle werden Möglichkeiten zur Ermittlung des notwendigen Umfangs basierend auf den vorliegenden Daten vorgestellt. Die verschiedenen flexiblen Designs werden für diese Art von Beobachtungen ausgiebig in Simulationsstudien untersucht. Insbesondere von Interesse ist hierbei, ob Prüfgrößen, welche bereits im nicht-sequentiellen Fall das Testniveau nur asymptotisch einhalten, in adaptiven Designs Anwendung finden können

Anti-acid therapy in idiopathic pulmonary fibrosis: insights from the INPULSIS (R) trials

Background: The benefits and risks of anti-acid medication in patients with idiopathic pulmonary fibrosis (IPF) remain a topic of debate. We investigated whether use of anti-acid medication at baseline was associated with differences in the natural course of disease or influenced the treatment effect of nintedanib in patients with IPF. Methods: Post-hoc analyses of outcomes in patients receiving versus not receiving anti-acid medication (proton pump or histamine-2 receptor inhibitor) at baseline using pooled data from the two Phase III randomized placebo-controlled INPULSIS (R) trials of nintedanib in patients with IPF. Results: At baseline, 406 patients were receiving anti-acid medication (244 nintedanib;162 placebo) and 655 were not (394 nintedanib;261 placebo). In an analysis of the natural course of IPF by anti-acid medication use at baseline, the adjusted annual rate of decline in FVC was -252.9 mL/year in placebo-treated patients who were receiving anti-acid medication at baseline and -205.4 mL/year in placebo-treated patients who were not (difference of -47.5 mL/year [95% CI: -105.1, 10.1];p = 0.1057). In an analysis of the potential influence of anti-acid medication use on the treatment effect of nintedanib, the adjusted annual rates of decline in FVC were -124.4 mL/year in the nintedanib group and 252.9 mL/year in the placebo group (difference of 128.6 mL/year [95% CI: 74.9, 182.2]) in patients who were receiving anti-acid medication at baseline and -107.0 mL/year in the nintedanib group and -205.3 mL/year in the placebo group (difference of 98.3 mL/year [95% CI: 54.1, 142.5]) in patients who were not (treatment-by-time-by-subgroup interaction p = 0.3869). The proportions of patients who had >= 1 investigator-reported acute exacerbation were 11.7% and 5.0% in placebo-treated patients, and 4.9% and 4.8% of nintedanib-treated patients, among patients who were and were not receiving anti-acid medication at baseline, respectively. Conclusions: In post-hoc analyses of data from the INPULSIS (R) trials, anti-acid medication use at baseline was not associated with a more favorable course of disease, and did not impact the treatment effect of nintedanib, in patients with IPF

Analysis of body mass index, weight loss and progression of idiopathic pulmonary fibrosis

Background: Nintedanib is an approved therapy for idiopathic pulmonary fibrosis (IPF). Some patients treated with nintedanib experience weight loss. Exploratory data suggest that low body mass index or weight loss are associated with worse outcomes in patients with IPF. We investigated whether BMI at baseline or weight loss over 52 weeks was associated with FVC decline, or influenced the effect of nintedanib, in patients with IPF. Methods: Using pooled data from the two INPULSIS trials, we analysed the rate of decline in FVC (mL/yr) over 52 weeks in patients treated with nintedanib and placebo in subgroups by baseline BMI ( 5%) using random coefficient regression. Results: In the placebo group, the mean rate of FVC decline over 52 weeks was numerically greater in patients with lower baseline BMI (− 283.3 [SE 22.4], − 207.9 [20.9] and − 104.5 [21.4] in patients with BMI 5% than ≤5% weight loss over 52 weeks (− 312.7 [SE 32.2] versus − 199.5 [SE 14.4] mL/year). Nintedanib reduced the rate of FVC decline versus placebo in both subgroups by weight loss, with a greater treatment effect in patients with > 5% weight loss (interaction p = 0.0008). The adverse event profile of nintedanib was similar across subgroups. Conclusions: In patients with IPF, lower BMI and weight loss may be associated with faster decline in FVC. Nintedanib reduces the rate of FVC decline both in patients who lose weight on treatment and those who do not. Trial registration: ClinicalTrials.gov; Nos. NCT01335464 and NCT01335477; URL: www.clinicaltrials.gov

First Data on Efficacy and Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis and Forced Vital Capacity of ≤50 % of Predicted Value

In the Phase III INPULSIS(®) trials, 52 weeks' treatment with nintedanib reduced decline in forced vital capacity (FVC) versus placebo in patients with idiopathic pulmonary fibrosis (IPF). Patients who completed the INPULSIS(®) trials could receive nintedanib in an open-label extension trial (INPULSIS(®)-ON). Patients with FVC 50 % predicted at the start of INPULSIS(®)-ON, the absolute mean change in FVC from baseline to week 48 of INPULSIS(®)-ON was -62.3 and -87.9 mL, respectively (n = 24 and n = 558, respectively). No new safety signals were identified in INPULSIS(®)-ON compared with INPULSIS(®). The decline in FVC in INPULSIS(®)-ON in both subgroups by baseline FVC % predicted was similar to that in INPULSIS(®), suggesting that nintedanib may have a similar effect on disease progression in patients with advanced disease as in less advanced disease.status: publishe

Efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis who are elderly or have comorbidities

Idiopathic pulmonary fibrosis (IPF) predominantly affects individuals aged > 60 years who have several comorbidities. Nintedanib is an approved treatment for IPF, which reduces the rate of decline in forced vital capacity (FVC). We assessed the efficacy and safety of nintedanib in patients with IPF who were elderly and who had multiple comorbidities. Data were pooled from five clinical trials in which patients were randomised to receive nintedanib 150 mg twice daily or placebo. We assessed outcomes in subgroups by age  3 at baseline. The data set comprised 1690 patients. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks versus placebo in patients aged ≥ 75 years (difference: 105.3 [95% CI 39.3, 171.2]) (n = 326) and  3 (difference: 129.5 [57.6, 201.4]) (n = 360) (p = 0.57 for treatment-by-time-by-subgroup interaction). The adverse event profile of nintedanib was generally similar across subgroups. The proportion of patients with adverse events leading to treatment discontinuation was greater in patients aged ≥ 75 years than < 75 years in both the nintedanib (26.4% versus 16.0%) and placebo (12.2% versus 10.8%) groups. Similarly the proportion of patients with adverse events leading to treatment discontinuation was greater in patients with ≥ 5 than < 5 comorbidities (nintedanib: 20.5% versus 15.7%; placebo: 12.1% versus 10.0%). Our findings suggest that the effect of nintedanib on reducing the rate of FVC decline is consistent across subgroups based on age and comorbidity burden. Proactive management of adverse events is important to reduce the impact of adverse events and help patients remain on therapy. ClinicalTrials.gov NCT00514683, NCT01335464, NCT01335477, NCT02788474, NCT01979952

Association between weight loss and decline in FVC in patients with IPF

International audienceIntroductionWeight loss has been associated with worse survival in patients with idiopathic pulmonary fibrosis (IPF).AimTo assess the association between weight loss and disease progression measured as decline in forced vital capacity (FVC) in patients with IPF in the INPULSIS trials.MethodsIn post-hoc analyses, we assessed the rate of decline in FVC (mL/yr) over 52 weeks in subgroups by weight loss from baseline over 52 weeks (weight gain/no weight loss; 0 to ≤ 5% weight loss; > 5 to ≤ 10% weight loss; > 10% weight loss) using random coefficient regression.ResultsAmong 421 patients in the placebo group, the proportions with no, 0 to ≤ 5%, > 5 to ≤ 10% and > 10% weight loss over 52 weeks were 45.6%, 34.7%, 13.1% and 6.7%, respectively. At baseline, subgroups with greater weight loss over 52 weeks had a higher mean age, lower proportion of males, lower mean DLco % predicted and lower mean FVC % predicted. In the placebo group, the mean rate of decline in FVC over 52 weeks increased with increasing weight loss ([Fig. 1]). In contrast, similar rates of decline in FVC were observed in nintedanib-treated patients (n = 635) irrespective of weight loss.ConclusionIn the INPULSIS trials, patients with greater weight loss showed faster disease progression when treated with placebo, and a more pronounced treatment effect of nintedanib

Relationship between body mass index (BMI) and decline in FVC in patients with IPF

International audienceIntroductionLower BMI may be associated with worse prognosis in patients with IPF.AimTo assess the association between BMI at baseline and decline in FVC in patients with IPF in the INPULSIS trials.MethodsIn post-hoc analyses, we assessed the rate of decline in FVC (mL/yr) over 52 weeks in subgroups of patients by BMI below and above the median of the trial population at baseline (27 kg/m2) using random coefficient regression.ResultsAt baseline, mean FVC was similar between patients with BMI < 27 kg/m2 (n = 486; mean BMI: 24.1) and ≥ 27 kg/m2 (n = 575; mean BMI: 31.1) (2696 and 2739 mL, respectively). Compared with patients with BMI ≥ 27 kg/m2, those with BMI < 27 kg/m2 had lower mean DLco (45.8% vs. 48.5% predicted), and greater proportions were of Asian race (51% vs. 13%), had never smoked (31% vs. 26%) and had emphysema (44% vs. 35%). In the placebo group, the mean [SE] rate of decline in FVC over 52 weeks was greater in patients with BMI < vs. ≥ 27 kg/m2 (− 266.24 [18.68] vs. − 183.06 [19.11] mL/yr). In the nintedanib group, the mean [SE] rate of decline in FVC was similar in patients with BMI < vs. ≥ 27 kg/m2 (− 108.48 [16.24] vs. − 117.69 [14.82] mL/yr, respectively).ConclusionIn the INPULSIS trials, patients with BMI below the median at baseline showed faster disease progression when treated with placebo, and a more pronounced treatment effect of nintedanib, compared to patients with BMI above the median at baseline

Reliability of operational data from pig herds and performance ratings by veterinarians and pig farmers collected during telephone interviews for the evaluation of a PCV2 piglet vaccination

BackgroundThe aim of the present study was to evaluate the feasibility of using a telephone survey in gaining an understanding of the possible herd and management factors influencing the performance (i.e. safety and efficacy) of a vaccine against porcine circovirus type 2 (PCV2) in a large number of herds and to estimate customers¿ satisfaction.ResultsDatasets from 227 pig herds that currently applied or have applied a PCV2 vaccine were analysed. Since 1-, 2- and 3-site production systems were surveyed, the herds were allocated in one of two subsets, where only applicable variables out of 180 were analysed. Group 1 was comprised of herds with sows, suckling pigs and nursery pigs, whereas herds in Group 2 in all cases kept fattening pigs. Overall 14 variables evaluating the subjective satisfaction with one particular PCV2 vaccine were comingled to an abstract dependent variable for further models, which was characterized by a binary outcome from a cluster analysis: good/excellent satisfaction (green cluster) and moderate satisfaction (red cluster). The other 166 variables comprised information about diagnostics, vaccination, housing, management, were considered as independent variables. In Group 1, herds using the vaccine due to recognised PCV2 related health problems (wasting, mortality or porcine dermatitis and nephropathy syndrome) had a 2.4-fold increased chance (1/OR) of belonging to the green cluster. In the final model for Group 1, the diagnosis of diseases other than PCV2, the reason for vaccine administration being other than PCV2-associated diseases and using a single injection of iron had significant influence on allocating into the green cluster (P¿<¿0.05). In Group 2, only unchanged time or delay of time of vaccination influenced the satisfaction (P¿<¿0.05).ConclusionThe methodology and statistical approach used in this study were feasible to scientifically assess ¿satisfaction¿, and to determine factors influencing farmers¿ and vets¿ opinion about the safety and efficacy of a new vaccine

Analysis of body mass index, weight loss and progression of idiopathic pulmonary fibrosis

International audienceBACKGROUND: Nintedanib is an approved therapy for idiopathic pulmonary fibrosis (IPF). Some patients treated with nintedanib experience weight loss. Exploratory data suggest that low body mass index or weight loss are associated with worse outcomes in patients with IPF. We investigated whether BMI at baseline or weight loss over 52 weeks was associated with FVC decline, or influenced the effect of nintedanib, in patients with IPF.METHODS: Using pooled data from the two INPULSIS trials, we analysed the rate of decline in FVC (mL/yr) over 52 weeks in patients treated with nintedanib and placebo in subgroups by baseline BMI (&lt; 25; ≥25 to &lt; 30; ≥30 kg/m(2)) and by weight loss over 52 weeks (≤5; &gt; 5%) using random coefficient regression.RESULTS: In the placebo group, the mean rate of FVC decline over 52 weeks was numerically greater in patients with lower baseline BMI (- 283.3 [SE 22.4], - 207.9 [20.9] and - 104.5 [21.4] in patients with BMI &lt; 25 kg/m(2), ≥25 to &lt; 30 kg/m(2) and ≥ 30 kg/m(2), respectively). Nintedanib reduced the rate of FVC decline versus placebo in all subgroups by BMI, with a consistent treatment effect across subgroups (interaction p = 0.31). In the placebo group, the mean rate of FVC decline was numerically greater in patients with &gt; 5% than ≤5% weight loss over 52 weeks (- 312.7 [SE 32.2] versus - 199.5 [SE 14.4] mL/year). Nintedanib reduced the rate of FVC decline versus placebo in both subgroups by weight loss, with a greater treatment effect in patients with &gt; 5% weight loss (interaction p = 0.0008). The adverse event profile of nintedanib was similar across subgroups.CONCLUSIONS: In patients with IPF, lower BMI and weight loss may be associated with faster decline in FVC. Nintedanib reduces the rate of FVC decline both in patients who lose weight on treatment and those who do not. TRIAL REGISTRATION: ClinicalTrials.gov ; Nos. NCT01335464 and NCT01335477 ; URL: www.clinicaltrials.gov

Health-related quality of life and symptoms in patients with IPF treated with nintedanib: analyses of patient-reported outcomes from the INPULSIS (R) trials

BACKGROUND: In the Phase III INPULSIS® trials, treatment of patients with idiopathic pulmonary fibrosis (IPF) with nintedanib significantly reduced the annual rate of decline in forced vital capacity (FVC) versus placebo, consistent with slowing disease progression. However, nintedanib was not associated with a benefit in health-related quality of life (HRQoL) assessed using the St George's respiratory questionnaire (SGRQ). We aimed to further examine the impact of IPF progression on HRQoL and symptoms, and to explore the effect of nintedanib on HRQoL in patients from the INPULSIS® trials stratified by clinical factors associated with disease progression. METHODS: Patient-reported outcome (PRO) data from the INPULSIS® trials were included in three post hoc analyses. Two analyses used the pooled data set to examine PRO changes from baseline to week 52 according to 1) decline in FVC and 2) occurrence of acute exacerbations. In the third analysis, patients were stratified based on clinical indicators of disease progression (gender, age and physiology [GAP] stage; FVC % predicted; diffusing capacity of the lung for carbon monoxide [DLCO] % predicted; composite physiologic index [CPI]; and SGRQ total score) at baseline; median change from baseline was measured at 52 weeks and treatment groups were compared using the Wilcoxon two-sample test. RESULTS: Data from 1061 patients (638 nintedanib, 423 placebo) were analyzed. Greater categorical decline from baseline in FVC % predicted over 52 weeks was associated with significant worsening of HRQoL and symptoms across all PRO measures. Acute exacerbations were associated with deterioration in HRQoL and worsened symptoms. In general, patients with advanced disease at baseline (defined as GAP II/III, FVC ≤ 80%, DLCO ≤ 40%, CPI >  45, or SGRQ > 40) experienced greater deterioration in PROs than patients with less-advanced disease. Among patients with advanced disease, compared with placebo, nintedanib slowed deterioration in several PROs; benefit was most apparent on the SGRQ (total and activity scores). CONCLUSIONS: In patients with advanced IPF, compared with placebo, nintedanib slowed deterioration in HRQoL and symptoms as assessed by several PROs. HRQoL measures have a higher responsiveness to change in advanced disease and may lack sensitivity to capture change in patients with less-advanced IPF.status: publishe