The effect of aclidinium bromide on daily respiratory symptoms of COPD, measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) diary: pooled analysis of two 6-month Phase III studies.

BACKGROUND: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS). METHODS: Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed. RESULTS: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D. CONCLUSIONS: Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms. TRIAL REGISTRATION: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 )

Stage 1 Development of a Patient Reported Experience Measure (PREM) for Chronic Obstructive Pulmonary Disease (COPD)

The study aimed to explore patients’ experience of living with COPD and their perspective of their community health care for COPD to extract affective responses in order to develop potential items for a patient reported experience measure (PREM) for Chronic Obstructive Pulmonary Disease (COPD). Qualitative face-face interviews were conducted, in the community, with 64 patients with COPD recruited from General Practices and Breath-Easy community groups in the Outer North East, East and City, London and Essex, UK. A two phase analysis of the qualitative data was conducted to identify themes arising from patients’ description of living with COPD and their perceptions of their community health care and subsequently the affective responses underlying the themes raised by patients, which gave emotional colour to the themes, bringing the thematic analysis closer to the subjective patient experience. Five themes were identified from the interview data: ‘Journey to diagnosis’; ‘Smoking’; ‘Usual care’; ‘My everyday life’; and ‘Exacerbations’. Twenty affective responses were identified and categorised as either ‘negative’, ‘positive’ or ‘bivalent’. ‘Frustration’, a negative affective response was prevalent in four themes. ‘Gratitude’, ‘hope’ and ‘happiness/enjoyment’ were among the more positive responses more prevalent across several themes. By conducting a novel two-way analysis (thematic and affective) it was possible to identify themes and affective responses that were aligned to those themes. This enabled the development of 38 COPD specific experience items to take forward for further testing including item reduction and validity and reliability in the next stage of the PREM development

Development of the chronic obstructive pulmonary disease morning symptom diary (COPD-MSD).

BACKGROUND: The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one's ability to perform even simple activities. Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD. A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials. METHODS: A qualitative interview study was conducted among a sample of symptomatic adults with COPD. Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD). All interview transcript data were coded using ATLAS.ti software for content analysis. RESULTS: Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively. The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement. During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %). A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD. Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand. The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary. CONCLUSIONS: This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing

The FDA guidance for industry on PROs: the point of view of a pharmaceutical company

The importance of the patients point of view on their health status is widely recognised. Patient-reported outcomes is a broad term encompassing a large variety of different health data reported by patients, as symptoms, functional status, Quality of Life and Health-Related Quality of Life. Measurements of Health-Related Quality of Life have been developed during many years of researches, and a lot of validated questionnaires exist. However, few attempts have been made to standardise the evaluation of instruments characteristics, no recommendations are made about interpretation on Health-Related Quality of Life results, especially regarding the clinical significance of a change leading a therapeutic approach. Moreover, the true value of Health-Related Quality of Life evaluations in clinical trials has not yet been completely defined. An important step towards a more structured and frequent use of Patient-Reported Outcomes in drug development is represented by the FDA Guidance, issued on February 2006. In our paper we aim to report some considerations on this Guidance. Our comments focus especially on the characteristics of instruments to use, the Minimal Important Difference, and the methods to calculate it. Furthermore, we present the advantages and opportunities of using the Patient-Reported Outcomes in drug development, as seen by a pharmaceutical company. The Patient-Reported Outcomes can provide additional data to make a drug more competitive than others of the same pharmacological class, and a well demonstrated positive impact on the patient' health status and daily life might allow a higher price and/or the inclusion in a reimbursement list. Applying extensively the FDA Guidance in the next trials could lead to a wider culture of subjective measurement, and to a greater consideration for the patient's opinions on his/her care. Moreover, prescribing doctors and payers could benefit from subjective information to better define the value of drugs

Gender and respiratory factors associated with dyspnea in chronic obstructive pulmonary disease

RATIONALE: We had shown that COPD women expressed more dyspnea than men for the same degree of airway obstruction. OBJECTIVES: Evaluate gender differences in respiratory factors associated with dyspnea in COPD patients. METHODS: In a FEV(1 )% matched population of 100 men and women with COPD we measured: age, MMRC, FEV(1), FVC, TLC, IC/TLC, PaO(2), PaCO(2), D(LCO), P(imax), P(0.1), Ti/Ttot, BMI, ffmi, 6MWD and VAS scale before and after the test, the Charlson score and the SGRQ. We estimated the association between these parameters and MMRC scores. Multivariate analysis determined the independent strength of those associations. RESULTS: MMRC correlated with: BMI (men:-0.29, p = 0.04; women:-0.28, p = 0.05), ffmi (men:-0.39, p = 0.01), FEV(1 )% (men:-0.64, p < 0.001; women:-0.29, p = 0.04), FVC % (men:-0.45, p = 0.001; women:-0.33, p = 0.02), IC/TLC (men:-0.52, p < 0.001; women: -0.27, p = 0.05), PaO(2 )(men:-0.59, p < 0.001), PaCO(2 )(men:0.27, p = 0.05), D(LCO )(men:-0.54, p < 0.001), P(0.1)/P(imax )(men:0.46, p = 0.002; women:0.47, p = 0.005), dyspnea measured with the Visual Analog Scale before (men:0.37, p = 0.04; women:0.52, p = 0.004) and after 6MWD (men:0.52, p = 0.002; women:0.48, p = 0.004) and SGRQ total (men:0.50, p < 0.001; women:0.59, p < 0.001). Regression analysis showed that P(0.1)/P(imax )in women (r(2 )= 0.30) and BMI, DL(CO), PaO(2 )and P(0.1)/P(imax )in men (r(2 )= 0.81) were the strongest predictors of MMRC scores. CONCLUSION: In mild to severe COPD patients attending a pulmonary clinic, P(0.1)/P(imax )was the unique predictor of MMRC scores only in women. Respiratory factors explain most of the variations of MMRC scores in men but not in women. Factors other than the respiratory ones should be included in the evaluation of dyspnea in women with COPD

Cost minimization analysis of different growth hormone pen devices based on time-and-motion simulations

<p>Abstract</p> <p>Background</p> <p>Numerous pen devices are available to administer recombinant Human Growth Hormone (rhGH), and both patients and health plans have varying issues to consider when selecting a particular product and device for daily use. Therefore, the present study utilized multi-dimensional product analysis to assess potential time involvement, required weekly administration steps, and utilization costs relative to daily rhGH administration.</p> <p>Methods</p> <p>Study objectives were to conduct 1) Time-and-Motion (TM) simulations in a randomized block design that allowed time and steps comparisons related to rhGH preparation, administration and storage, and 2) a Cost Minimization Analysis (CMA) relative to opportunity and supply costs. Nurses naïve to rhGH administration and devices were recruited to evaluate four rhGH pen devices (2 in liquid form, 2 requiring reconstitution) via TM simulations. Five videotaped and timed trials for each product were evaluated based on: 1) Learning (initial use instructions), 2) Preparation (arrange device for use), 3) Administration (actual simulation manikin injection), and 4) Storage (maintain product viability between doses), in addition to assessment of steps required for weekly use. The CMA applied micro-costing techniques related to opportunity costs for caregivers (categorized as wages), non-drug medical supplies, and drug product costs.</p> <p>Results</p> <p>Norditropin^®NordiFlex and Norditropin^®NordiPen (NNF and NNP, Novo Nordisk, Inc., Bagsværd, Denmark) took less weekly Total Time (p < 0.05) to use than either of the comparator products, Genotropin^®Pen (GTP, Pfizer, Inc, New York, New York) or HumatroPen^®(HTP, Eli Lilly and Company, Indianapolis, Indiana). Time savings were directly related to differences in new package Preparation times (NNF (1.35 minutes), NNP (2.48 minutes) GTP (4.11 minutes), HTP (8.64 minutes), p < 0.05)). Administration and Storage times were not statistically different. NNF (15.8 minutes) and NNP (16.2 minutes) also took less time to Learn than HTP (24.0 minutes) and GTP (26.0 minutes), p < 0.05). The number of weekly required administration steps was also least with NNF and NNP. Opportunity cost savings were greater in devices that were easier to prepare for use; GTP represented an 11.8% drug product savings over NNF, NNP and HTP at time of study. Overall supply costs represented <1% of drug costs for all devices.</p> <p>Conclusions</p> <p>Time-and-motion simulation data used to support a micro-cost analysis demonstrated that the pen device with the greater time demand has highest net costs.</p