Michael C Nivens

Boehringer Ingelheim, Ingelheim, Rheinland-Pfalz, Germany

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Publications (6)25.35 Total impact

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    ABSTRACT: The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 second (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1·65%), 3.59% (1·60%) and 3.98% (1·64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1·68%) for fluticasone 220 μg bid (p = 0·0311, p = 0·0126, p = 0·0078 and p < 0·0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1·49%) for BI 671800 400 mg bid and 2.37% (1·57%) for montelukast (p = 0·0050 and p = 0·0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS. Copyright © 2015. Published by Elsevier Ltd.
    Pulmonary Pharmacology &amp Therapeutics 04/2015; 227. DOI:10.1016/j.pupt.2015.03.003 · 2.94 Impact Factor
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    ABSTRACT: To correctly estimate the cost-effectiveness of treatments that reduce COPD exacerbations, the utility gains from preventing exacerbations need to be measured. This requires utility measurement during exacerbations. To assess the ability of the EQ-5D to detect the recovery from moderate COPD exacerbations. In the US, 65 COPD and/or chronic bronchitis patients (≥40 years old smokers or ex-smokers with a history of 10 pack-years) were enrolled within 48 h of symptom onset of the exacerbation. Patients completed the EQ-5D at enrollment and after 7, 14 and 42 days. Symptoms and medication use were recorded in diaries. Change over time and loss of quality-adjusted life years (QALYs) due to the exacerbation was estimated. Using standardized response mean (SRM) as the metric of responsiveness, we compared the responsiveness of the EQ-5D to the responsiveness of morning peak expiratory flow rate, rescue medication use and symptom scores. SRMs were also used to assess whether patients with greater improvements in peak expiratory flow rate, rescue medication use, symptom scores, clinician global impression of change, and patient global impression of change had a greater improvement in EQ-5D than patients with smaller improvement. Mean utility index scores (standard deviation) using the US value set were 0.683 (0.209), 0.726 (0.216), 0.768 (0.169) and 0.760 (0.181) at days 1, 7, 14 and 42, respectively. The mean of each patient's lowest index score, either at visit 1 or visit 2, was 0.651 (0.213). Over the course of 6 weeks there was a highly significant improvement in mean utility. The greatest improvement was seen between day 7 and day 14. Patients lost on average 0.00896 QALY (0.0086) or 3.27 (3.13) quality-adjusted life days during the exacerbation. The EQ-5D (SRM: 0.653) was more responsive to change than peak expiratory flow (0.269), rescue medication use (0.343) and sputum symptom scores (0.322) and equally responsive as cough (0.587) and dyspnea (0.638) symptom scores. The EQ-5D is responsive to the recovery from a moderate COPD exacerbation.
    Respiratory medicine 03/2011; 105(8):1195-202. DOI:10.1016/j.rmed.2011.02.018 · 3.09 Impact Factor
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    ABSTRACT: The question whether epidermal growth factor (EGF)-induced receptor endocytosis requires the prior autophosphorylation via the EGF receptor (EGFR) kinase domain has been a matter of long-standing debate. In the airway epithelial cell line NCI-H292, the EGFR kinase domain inhibitor BIBW 2948 BS was found to inhibit both autophosphorylation and subsequent internalization of the endogenous EGFR with similar IC₅₀ values. Applying an ex vivo EGFR internalization assay in a clinical study, the in vivo effect of inhalatively administered BIBW 2948 BS was determined directly at the targeted receptor in airway tissues from COPD patients. In these experiments, the in vivo inhibition of the EGFR kinase domain prevented the EGF-induced internalization of EGFR.
    Experimental Cell Research 01/2011; 317(1):42-50. DOI:10.1016/j.yexcr.2010.09.009 · 3.25 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) activation is implicated in mucin hypersecretion in chronic obstructive pulmonary disease (COPD). To investigate the safety and efficacy of an inhaled EGFR antagonist (BIBW 2948) in COPD. Multicenter, double-blind, placebo-controlled trial of 4 weeks of treatment with two doses of BIBW 2948 (15 and 30 mg twice a day) on safety and mucin-related outcomes in 48 patients with COPD. The effect of BIBW 2948 on EGFR activation in airway epithelial cells was assessed using an ex vivo assay. Efficacy measures included the volume of mucin in the airway epithelium (Vs mu,bala) in bronchial biopsies and the expression of mucin genes in bronchial brushings. Inhaled BIBW 2948 induced a dose-related inhibition of EGFR internalization (reflecting decreased EGFR activation) in epithelial cells from treated subjects. However, BIBW 2948 was associated with a dose-related increase in adverse events, including reversible liver enzyme elevation (n = 2), and reduction in FEV(1). The changes in mucin stores and mucin gene expression were not significantly different in the pooled BIBW 2948 group versus placebo (volume of mucin per surface area of basal lamina = 0.22 +/- 7.11 vs. 0.47 +/- 8.06 microm(3)/microm(2); P = 0.93). However, in the 30 mg twice a day group, the reduction in epithelial mucin stores was greatest in subjects with the greatest degree of EGFR inhibition (Pearson r = 0.98; 95% confidence interval, 0.71-0.99). Four-week treatment with BIBW 2948 did not significantly decrease epithelial mucin stores and was poorly tolerated in patients with COPD. Ex vivo analyses suggest that higher doses may be more effective at both EGFR inhibition and decreases in mucin stores but that adverse events should be expected. Clinical trial registered with www.clinicaltrials.gov (NCT00423137).
    American Journal of Respiratory and Critical Care Medicine 12/2009; 181(5):438-45. DOI:10.1164/rccm.200909-1415OC · 13.00 Impact Factor
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    ABSTRACT: To assess the responsiveness of the Cough and Sputum Assessment Questionnaire (CASA-Q) in COPD and chronic bronchitis patients recovering from an acute exacerbation. The 20-item questionnaire with a 7-day recall assesses the frequency and severity of cough and sputum and their impact on everyday life in clinical (trial) settings. The four domains (cough/sputum symptom and impact) use scales from 0 to 100, with lower scores indicating higher symptom/impact levels. Outpatients were enrolled within 48h of symptom onset of their exacerbation. Treatment was initiated at the discretion of the investigator, and patients observed for 6 weeks. During study visits, 59 eligible patients completed the CASA-Q at enrolment, week 1, 2 and 6. Responsiveness was assessed by calculating standardized effect sizes. Of the 19 male and 40 female patients with a mean (standard deviation, SD) age of 61.1 (10.5) years, all were classified by their physician to have improved or recovered after six weeks. The mean (SD) CASA-Q sores for the cough symptom, cough impact, sputum symptom and sputum impact domains increased from 32.6 (21.0), 40.7 (22.4), 37.4 (20.1), 47.1 (24.2) at enrolment to 54.0 (19.8), 63.7 (21.3), 55.1 (19.0), 65.5 (20.5) at week 6, respectively. Standardized effect sizes for patients improved or recovered from their exacerbation at week 6 were above 1.0 for the cough domains and at least 0.77 for the sputum domains. The CASA-Q was responsive to symptom changes in patients recovering from an exacerbation.
    Respiratory medicine 11/2009; 104(4):534-41. DOI:10.1016/j.rmed.2009.10.026 · 3.09 Impact Factor
  • K Tetzlaff · P Sachs · J McDonald · B Crawford · MC Nivens · B Monz
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009