Randomised controlled trial for emphysema with a selective agonist of the γ-type retinoic acid receptor.

Palovarotene is an oral γ-selective retinoid agonist. In animal emphysema models, palovarotene reduced inflammation, promoted structural repair and functional improvement. REPAIR (Retinoid treatment of Emphysema in Patients on the α(1)-antitrypsin International Registry), was an investigator-initiated, double-blind, placebo-controlled randomised study to assess the safety and efficacy of 5 mg·day(-1) palovarotene given for 1 year to 262 patients with severe α(1)-antitrypsin deficiency and emphysema confirmed by computed tomography. Change in volume-adjusted 15th percentile point lung density from baseline in 1 year was the primary end-point; functional end-points were also regularly assessed. We randomly assigned 133 and 129 patients to placebo or palovarotene, respectively. Both groups were well matched for all baseline characteristics, including respiratory medications. 88% and 85% of patients completed 1 year of treatment with placebo and palovarotene, respectively. Palovarotene was generally well tolerated. In the study completers population, the placebo-corrected difference of lung density was -0.45 HU at week 28 (p=0.64) and -0.25 HU at week 52 (p=0.94). A nonsignificant treatment difference in most functional parameters of the lung in favour of the drug was observed over time suggesting potential pharmacological effects of palovarotene. Palovarotene 5 mg·day(-1) over 1 yr failed to show a significant benefit on lung density in moderate-to-severe emphysema secondary to severe α(1)-antitrypsin deficiency.

Matrix metalloproteinase-9 predicts pulmonary status declines in α1-antitrypsin deficiency.

BACKGROUND: Matrix metalloproteinase-9 (MMP-9) may be important in the progression of emphysema, but there have been few longitudinal clinical studies of MMP-9 including pulmonary status and COPD exacerbation outcomes. METHODS: We utilized data from the placebo arm (n=126) of a clinical trial of patients with alpha1-antitrypsin deficiency (AATD) and emphysema to examine the links between plasma MMP-9 levels, pulmonary status, and COPD exacerbations over a one year observation period. Pulmonary function, computed tomography lung density, incremental shuttle walk test (ISWT), and COPD exacerbations were assessed at regular intervals over 12 months. Prospective analyses used generalized estimating equations to incorporate repeated longitudinal measurements of MMP-9 and all endpoints, controlling for age, gender, race-ethnicity, leukocyte count, and tobacco history. A secondary analysis also incorporated highly-sensitive C-reactive protein levels in predictive models. RESULTS: At baseline, higher plasma MMP-9 levels were cross-sectionally associated with lower FEV1 (p=0.03), FVC (p<0.001), carbon monoxide transfer factor (p=0.03), resting oxygen saturation (p=0.02), and ISWT distance walked (p=0.02) but were not associated with radiographic lung density or total lung capacity (TLC). In longitudinal analyses, MMP-9 predicted a further decline in transfer factor (p=0.04) and oxygen saturation (p<0.001). MMP-9 also predicted worsening lung density (p=0.003), increasing TLC (p=0.02), and more frequent COPD exacerbations over follow-up (p=0.003). Controlling additionally for hs-CRP levels did not substantively change the longitudinal associations between MMP-9 and these outcomes. CONCLUSIONS: Increased plasma MMP-9 levels generally predicted pulmonary status declines, including worsening transfer factor and lung density as well as greater COPD exacerbations in AATD-associated emphysema.

Lazabemide, a selective, reversible monoamine oxidase B inhibitor, as an aid to smoking cessation.

BACKGROUND: Previous research has shown that smokers have reduced brain and platelet monoamine oxidase B (MAOB) activity. This is probably due to some components of tobacco smoke. When smokers quit, MAOB activity returns to normal. Reduced MAO activity may increase nicotine's addictive potential. AIMS: To assess whether lazabemide, a reversible selective MAOB inhibitor, promotes smoking cessation. STUDY DESIGN: Double-blind, randomized, placebo-controlled, multicenter phase II study. Placebo, lazabemide 100 mg/day and 200 mg/day were administered for 8 weeks. This was a dose finding, proof-of-concept, exploratory study. SETTING: General practices and anti-smoking clinics in France and Belgium. PARTICIPANTS: Smokers smoking > or=15 cigarettes per day and motivated to quit. MAIN OUTCOME MEASURE: Sustained abstinence during the last 4 weeks of the study. FINDINGS: The study was discontinued prematurely by the sponsor before randomization of the planned 420 smokers because of liver toxicity observed in other indications. Data of 330 randomized subjects could be analysed. Sustained abstinence during the last 4 weeks of treatment was 9%, 11% and 17% in the intent-to-treat population [P for trend: 0.036 (one-sided)]; 11%, 14% and 21% in the intent-to-treat population of smokers without those excluded because of discontinuation of the study [n = 262, P for trend: 0.02 (one-sided)], and 19%, 27% and 35% in completers [P for trend: 0.03 (one-sided)], in the placebo, lazabemide 100 mg/day and lazabemide 200 mg/day groups, respectively. Point prevalence abstinence (intent-to-treat population) at the end of treatment (week 8) was 17%, 19% and 30% in the placebo, lazabemide 100 mg/day and lazabemide 200 mg/day groups, respectively (placebo vs. lazabemide 200 mg/day: P = 0.01, one-sided). No treatment emergent major adverse event occurred. More nausea and insomnia were reported with lazabemide than with placebo. CONCLUSIONS: MAOB inhibitors are promising treatments as an aid in smoking cessation. There may be an interest to develop MAOB inhibitors with an acceptable toxicity profile. Further studies may associate MAOB inhibitors with nicotine replacement therapies to increase therapeutic efficacy.

The Modified Reasons for Smoking Scale: factorial structure, gender effects and relationship with nicotine dependence and smoking cessation in French smokers.

AIMS: To assess the validity of the French version of the Modified Reasons for Smoking Scale (MRSS), and to identify which smoking patterns differentiate male and female smokers, which are related to tobacco dependence (as assessed by the Fagerström Test for Nicotine Dependence, FTND), to mood (Beck Depression Inventory II), to affect (Positive and Negative Affect Schedule) and which are predictors of successful quitting. PARTICIPANTS: Three hundred and thirty smokers [(mean +/- SD) aged 40 +/- 9 years, 145 (44%) women, mean FTND score: 6.2 +/- 2], candidates for a smoking cessation programme and smoking at least 15 cigarettes/day. FINDINGS: Factor analysis of the 21-item scale gave the optimal fit for a seven-factor model, which accounted for 62.3% of the total variance. The following factors were identified: 'addictive smoking', 'pleasure from smoking', 'tension reduction/relaxation', 'social smoking', 'stimulation', 'habit/automatism' and 'handling'. The 'addictive smoking' score increased in a dose-dependent manner with number of cigarettes smoked per day; the 'habit/automatism' score was significantly higher, with more than 20 cigarettes per day than with < or = 20 cigarettes per day. The reasons for smoking were different for males and females: females scored higher on 'tension reduction/relaxation', 'stimulation' and 'social smoking'. A high level of dependence (FTND > or = 6) was associated with significantly higher scores only on 'addictive smoking', the association being stronger in females. Time to first cigarette after awakening was associated with higher 'addictive smoking' and 'habit/automatism' (P < 0.001). In a multivariate logistic regression, failed quitting was predicted by higher habit/automatism score (odds ratio = 1.44, 95% CI = 1.06-1.95, P = 0.02) and greater number of cigarettes smoked per day (odds ratio = 1.03, 95% CI = 1.01-1.06, p = 0.03). CONCLUSIONS: The questionnaire yielded a coherent factor structure; women smoked more for tension reduction/relaxation, stimulation and for social reasons than men; addictive smoking and automatic smoking behaviour were similar in both sexes and were associated strongly with a high level of nicotine dependence; the 'habit/automatism' score predicted failure to quit over and above cigarettes per day.

Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry. The REPAIR study: study design, methodology and quality control of study assessments.

Emphysema is characterized by the destruction of alveolar wall and enlargement of alveolar airspaces, resulting in a reduction of the total lung gas exchange area, loss of lung elastic recoil and hyperinflation. The REPAIR study (Retinoid treatment of Emphysema in Patients on the Alpha-1 International Registry) is the first proof-of-concept study of a new potential disease-modifying drug, Palovarotene©, an orally active, gamma selective retinoid agonist in patients with emphysema secondary to alpha-1-antitrypsin deficiency (AATD) as a model population for the general smoke-induced emphysema population. This article describes the study design as well as the effectiveness of the quality control that was implemented on the key efficacy endpoints, based on data derived from the placebo-treated subjects. In this multicentre, multinational study the implementation of standardized procedures included: careful site selection, use of trained staff, regular monitoring and machine calibration, use of biological controls and regular feedback to sites by an independent quality control centre. All of these procedures resulted in high-quality measurements of lung density, spirometry, static lung volumes and gas transfer. It was also confirmed that CT lung density was the most sensitive endpoint followed by TLco, FEV(1) and RV measured by body box.

Quality control in longitudinal studies with computed tomographic densitometry of the lungs.

To guarantee the reliability of densitometric data in clinical trials on pulmonary emphysema a quality control procedure is presented, to prevent that a measured progression in lung density could be reflected by a gradual change in the maintenance of the computed tomographic scanner. For that purpose, a foam phantom has been developed, which mimicks the densities of emphysematous lung tissue, fixed in a sealed Perspex box. Analysis software was developed to automatically compare the density readings with a baseline reference. It was found that this quality control procedure can pick up subtle changes in the scanner of less than 1 hounsfield unit, due to changes in the X-ray tube, detectors, or reconstruction software, and can detect certain imaging artifacts. Therefore, it is recommended that this type of procedure be used to ensure the integrity of densitometric data in longitudinal studies.