Development of the Myasthenia Gravis (MG) Symptoms PRO: a case study of a patient-centred outcome measure in rare disease.

BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disease, characterised by fluctuating muscle weakness which makes it challenging to assess symptom severity. Mixed methods psychometrics (MMP), which combines evidence from qualitative research and modern psychometrics, is a versatile approach to the development of patient-centred outcome measures (PCOM) in the context of rare disease. Our objective was to develop the MG Symptom patient-reported outcome (PRO) to assess key aspects of MG severity from the patient perspective. METHODS: We used MMP to develop a novel PRO instrument in a multi-step process. An initial conceptual model for MG patient experience was developed and expanded based on preliminary literature review and two waves of concept elicitation interviews with people with MG (Step 1). Based on this, the novel PRO instrument, the MG Symptoms PRO, was drafted. The draft instrument was refined by combining qualitative and quantitative data collected in a Phase 2 clinical study (Step 2). RESULTS: Findings from the literature review and concept elicitation interviews (n = 96) indicated that patient experience in MG includes proximal muscle weakness symptoms related to several body parts, along with muscle weakness fatigability and general fatigue. Then, a set of 42 items across five scales (ocular-, bulbar-, and respiratory muscle weakness, physical fatigue, and muscle weakness fatigability) was developed. Qualitative evidence endorsed its relevance, clarity, and ease of completion; quantitative analysis with Rasch measurement theory methods demonstrated strong measurement properties, including good targeting and high reliability. Classical test theory analyses showed adequate reliability of the instrument and mild to moderate correlations with other widely used MG-specific outcome measures. CONCLUSIONS: The MG Symptoms PRO has potential to be used both to measure treatment benefit in clinical trials and monitor symptom severity in clinical practice. Its component scales were purposefully designed to stand alone, enhancing interpretability of scores given the heterogeneity of MG, and enabling modular use. Compared with existing MG PROs, it contains more detailed assessments of muscle weakness and muscle weakness fatigability symptoms, which are of key importance to people with MG. The MMP approach used may serve as a case study for developing PCOMs across rare disease indications.

Patient-Centered Outcomes in ARIEL3, a Phase III, Randomized, Placebo-Controlled Trial of Rucaparib Maintenance Treatment in Patients With Recurrent Ovarian Carcinoma.

PURPOSE: To investigate quality-adjusted progression-free survival (QA-PFS) and quality-adjusted time without symptoms or toxicity (Q-TWiST) in a post hoc exploratory analysis of the phase III ARIEL3 study of rucaparib maintenance treatment versus placebo. PATIENTS AND METHODS: Patients with platinum-sensitive, recurrent ovarian carcinoma were randomly assigned to rucaparib (600 mg twice per day) or placebo. QA-PFS was calculated as progression-free survival function × the 3-level version of the EQ-5D questionnaire (EQ-5D-3L) index score function. Q-TWiST analyses were performed defining TOX as the mean duration in which a patient experienced grade ≥ 3 treatment-emergent adverse events (TEAEs) or the mean duration in which a patient experienced grade ≥ 2 TEAEs of nausea, vomiting, fatigue, and asthenia. Q-TWiST was calculated as µTOX × TOX + TWiST, with µTOX calculated using EQ-5D-3L data. RESULTS: The visit cutoff was Apr 15, 2017. Mean QA-PFS was significantly longer with rucaparib versus placebo in the intent-to-treat (ITT) population (375 randomly assigned to rucaparib v 189 randomly assigned to placebo; difference, 6.28 months [95% CI, 4.85 to 7.47 months]); BRCA-mutant cohort (130 rucaparib v 66 placebo; 9.37 months [95% CI, 6.65 to 11.85 months]); homologous recombination deficient (HRD) cohort (236 rucaparib v 118 placebo; 7.93 months [95% CI, 5.93 to 9.53 months]); and BRCA wild-type/loss of heterozygosity (LOH) low patient subgroup (107 rucaparib v 54 placebo; 2.71 months [95% CI, 0.31 to 4.44 months]). With TOX defined using grade ≥ 3 TEAEs, the difference in mean Q-TWiST (rucaparib v placebo) was 6.88 months (95% CI, 5.71 to 8.23 months), 9.73 months (95% CI, 7.10 to 11.94 months), 8.11 months (95% CI, 6.36 to 9.49 months), and 3.35 months (95% CI, 1.66 to 5.40 months) in the ITT population, BRCA-mutant cohort, HRD cohort, and BRCA wild-type/LOH low patient subgroup, respectively. Q-TWiST with TOX defined using select grade ≥ 2 TEAEs also consistently favored rucaparib. CONCLUSION: The significant differences in QA-PFS and Q-TWiST confirm the benefit of rucaparib versus placebo in all predefined cohorts.

Cost-effectiveness of roflumilast as an add-on treatment to long-acting bronchodilators in the treatment of COPD associated with chronic bronchitis in the United Kingdom.

OBJECTIVE: To estimate the cost-effectiveness of adding a selective phosphodiesterase-4 inhibitor, roflumilast, to a long-acting bronchodilator therapy (LABA) for the treatment of patients with severe-to-very severe chronic obstructive pulmonary disease (COPD) associated with chronic bronchitis with a history of frequent exacerbations from the UK payer perspective. METHODS: A Markov model was developed to predict the lifetime cost and outcomes [exacerbations rates, life expectancy, and quality-adjusted life years (QALY)] in patients treated with roflumilast, which showed a reduction in the exacerbation rates and lung function improvement in a pooled analysis from two clinical trials, M2-124 and M2-125. Sensitivity analyses were conducted to explore the impact of uncertainties on the cost-effectiveness. RESULTS: The addition of roflumilast to concomitant LABA reduced the number of exacerbations from 15.6 to 12.7 [2.9 (95 % CI 0.88-4.92) exacerbations avoided] and increased QALYs from 5.45 to 5.61 [0.16 (95 % CI 0.02-0.31) QALYs gained], at an incremental cost of £3,197 (95 % CI £2,135-£4,253). Cost in LABA alone and LABA + roflumilast were £16,161 and £19,358 respectively. The incremental cost-effectiveness ratios in the base case were £19,505 (95 % CI £364-£38,646) per quality-adjusted life-year gained and 18,219 (95 % CI £12,697-£49,135) per life-year gained. Sensitivity analyses suggest that among the main determinants of cost-effectiveness are the reduction of exacerbations and the case fatality rate due to hospital-treated exacerbations. Probabilistic sensitivity analysis suggests that the probability of roflumilast being cost-effective is 82 % at willingness-to-pay £30,000 per QALY. CONCLUSIONS: The addition of roflumilast to LABA in the treatment of patients with severe-to-very severe COPD reduces the rate of exacerbations and can be cost-effective in the UK setting.

Cost-effectiveness of varenicline compared with nicotine patches for smoking cessation--results from four European countries.

BACKGROUND: The aim of this study was to evaluate and compare the cost-effectiveness of varenicline with nicotine replacement therapy (NRT) for smoking cessation in four European countries (Belgium, France, Sweden and the UK). METHODS: Markov simulations, using the Benefits of Smoking Cessation on Outcomes (BENESCO) model, were performed. We simulated the incidence of four smoking-related morbidities: lung cancer, chronic obstructive pulmonary disease, coronary heart disease and stroke. The model computes quality-adjusted life-years gained and incremental cost-effectiveness ratios. Incremental cost-utility ratios were calculated, adopting a lifetime perspective. Efficacy data were obtained from a randomized open-label trial: Week 52 continuous abstinence rates were 26.1% for varenicline and 20.3% for NRT. RESULTS: The analyses imply that for countries analysed, smoking cessation using varenicline versus NRT was associated with reduced smoking-related morbidity and mortality. The number of morbidities avoided, per 1000 smokers attempting to quit, ranged from 9.7 in Belgium to 6.5 in the UK. The number of quality-adjusted life-years gained, per 1000 smokers, was 23 (Belgium); 19.5 (France); 29.9 (Sweden); and 23.7 (UK). In all base-case simulations (except France), varenicline dominated (more effective and cost saving) NRT regarding costs per quality-adjusted life-year gained; for France the incremental cost-effectiveness ratio was 2803. CONCLUSION: This cost-effectiveness analysis demonstrated that since varenicline treatment was more effective, the result was increased healthcare cost savings in Belgium, Sweden and the UK. Our results suggest that funding varenicline as a smoking cessation aid is justifiable from a healthcare resource allocation perspective.

Smoking-cessation therapy using varenicline: the cost-utility of an additional 12-week course of varenicline for the maintenance of smoking abstinence.

STUDY OBJECTIVES: To evaluate the cost-effectiveness of an additional 12-week treatment with varenicline for abstainers who had successfully completed an initial 12-week treatment. DESIGN: The Benefits of Smoking Cessation on Outcomes simulation model was used to simulate both direct and indirect effects of smoking cessation. All calculations were performed in 2003 Swedish prices. SETTING: Sweden in 2003. PATIENTS OR PARTICIPANTS: The modelled cohort consisted of 25% of adult smokers motivated to quit smoking (168,844 males and 208,737 females). The age and sex distributions of the cohort reflect that of the Swedish population in 2003. INTERVENTIONS: Smokers who had achieved abstinence for at least 7 days following 12-week open-label treatment with varenicline were randomized to receive an additional 12-week treatment with either varenicline or placebo. MEASUREMENTS AND RESULTS: The incremental costs per quality-adjusted life-year (QALY) gained, for abstainers who received an additional 12-week varenicline treatment compared with only 12 weeks, were Euro 7066 for men and Euro 7108 for women, over a 50-year time horizon. (1 Euro approximately equal to SEK 9.12). These estimates excluded indirect effects on production and consumption of increased survival. The corresponding incremental costs per QALY including indirect effects were Euro 24,149 and Euro 24,436, respectively. Sensitivity analysis indicated that the estimated cost-utility ratios are robust, but relatively sensitive to treatment efficiency and intervention costs. CONCLUSIONS: An additional 12-week course of varenicline treatment, provided to abstainers after an initial 12-week treatment, produces relatively low incremental cost-utility ratios in the spectrum of life-saving medical treatments.

Varenicline as compared to bupropion in smoking-cessation therapy--cost-utility results for Sweden 2003.

STUDY OBJECTIVES: To calculate incremental cost-utility ratios (cost per QALY gained) for varenicline (Champix; Pfizer), as compared to bupropion, in smoking-cessation programmes for a lifetime follow-up period. DESIGN: The Benefits of Smoking Cessation on Outcomes (BENESCO) simulation model was used for a male and female cohort, respectively, as a point of departure but further extended in order to include the indirect effects of smoking-cessation on production and consumption in the economy. All calculations were performed in 2003 Swedish prices. SETTING: Sweden in 2003. PATIENTS OR PARTICIPANTS: Model cohort consisting of 25% of all smokers among men and women (168,844 males and 208,737 females), distributed by age, 18 and older, as in the Swedish population of 2003. INTERVENTIONS: Varenicline as compared to bupropion, in smoking-cessation programmes for 20-year, 50-year, and lifetime follow-up periods. MEASUREMENTS AND RESULTS: When the indirect effects on production and consumption were included, the incremental costs per QALY gained were euro2056 (euro14,743) for men and euro1193 (euro14,214) for women, in comparison to bupropion and computed for a time horizon of 20 and 50 years (1euro approximately euroSEK9.12). Excluding the indirect effects on production and consumption, varenicline was cost-saving in comparison to bupropion. Sensitivity analysis indicated that the results are robust. Variation of treatment efficiency and intervention costs, respectively, had a larger effect on cost per QALY gained than other variables. CONCLUSIONS: Estimated costs per QALY gained rated smoking-cessation intervention using varenicline among the most cost-effective life-saving medical treatments.

Evaluating preference weights for the Asthma Symptom Utility Index (ASUI) across countries.

BACKGROUND: The Asthma Symptom Utility Index (ASUI) is a preference-based outcome measure used in US clinical trials and cost-effectiveness studies for asthma. This study evaluated ASUI preference weights in Europe to determine whether the multi-attribute utility function, based on preferences from a US population, is generalizable across countries. METHODS: Data were collected from ninety asthma patients from Italy, France, and the United Kingdom using the Asthma Control Questionnaire, the Asthma Quality of Life Questionnaire, and the ASUI. Subjects rated their preferences for 10 asthma health states using a visual analogue scale (VAS) and a standard gamble (SG) interview. RESULTS: All multi-symptom states showed statistically significant differences (p < 0.001) between countries in mean VAS scores. Mean SG utility scores between the US and France and the US and Italy demonstrated statistically significant differences (p < 0.001) for three states: severe wheeze; moderate cough and wheeze; and moderate cough and dyspnea. Because of these differences, the multi-attribute utility functions derived within countries were somewhat different. Despite these differences, country-specific algorithms captured a similar rank ordering of patients by disease severity, were strongly correlated (r = 0.971 to 0.995), and demonstrated similar relationships with symptom and AQLQ scores. CONCLUSION: Results of this study suggest that the ASUI may be a complementary patient-reported outcome for clinical studies and may be useful for applications in cost-effectiveness studies comparing different asthma treatments.

Modification of the asthma quality of life questionnaire (standardised) for patients 12 years and older.

BACKGROUND: The age limit for some adult asthma clinical trials has recently been lowered to 12 years. In this study we have made minor modifications to the standardised version of the adult Asthma Quality of Life Questionnaire (AQLQ(S)) to make it valid for patients 12 years and older (AQLQ12+). METHODS: We have used two clinical trial databases, in which the AQLQ12+ was used, to compare the measurement properties of the questionnaire in patients 12-17 years and patients 18 years and older. A total of 2433 patients (12-75 years), with current asthma and with data that could be evaluated both at randomisation and end of treatment, were included. RESULTS: The analysis showed that internal consistency, responsiveness and correlations with other clinical indices were very similar in patients 12-17 years and patients 18 years and older. CONCLUSION: The measurement properties of the AQLQ12+ are similar in adolescents and adults and therefore the instrument is valid for use in adult studies which include children 12 years and older.

Measurement properties and interpretation of three shortened versions of the asthma control questionnaire.

The Asthma Control Questionnaire (ACQ) measures the adequacy of asthma treatment as identified by international guidelines. It consists of seven items (5 x symptoms, rescue bronchodilator use and FEV1% of predicted normal). A validation study suggested that in clinical studies measurement of FEV1 and bronchodilator use may not be needed but this has never formally been tested in a clinical trial. The aims of this analysis were (1) to examine the measurement properties of three shortened versions of the ACQ (symptoms alone, symptoms plus FEV1 and symptoms plus short-acting beta2-agonist) and (2) to determine whether using the shortened versions would alter the results of a clinical trial. In the randomised trial, 552 adults completed the ACQ at baseline and after 13 and 26 weeks of treatment. The analysis showed that the measurement properties of all four versions of the ACQ are very similar. Agreement between the original ACQ and the reduced versions was high (intraclass correlation coefficients: 0.94-0.99). Mean differences between the ACQ and the shortened versions were less than 0.04 (on the 7-point scale). Clinical trial results using the four versions were almost identical with the mean treatment difference ranging from -0.09 (P=0.17), to -0.13 (P=0.07). For interpretability, the minimal important difference for all four versions was close to 0.5. In conclusion, these three shortened versions of the ACQ can be used in large clinical trials without loss of validity or change in interpretation.

Measuring health-related quality of life in adults during an acute asthma exacerbation.

BACKGROUND: Acute severe asthma can be distressing for patients. It is important to be able to identify the causes of the distress so that these can receive attention in conjunction with the conventional treatment of the airways. STUDY OBJECTIVE: To modify the Asthma Quality of Life Questionnaire (AQLQ) for evaluating patients with acute severe asthma and to test the measurement properties of the Acute Asthma Quality of Life Questionnaire (Acute AQLQ). METHODS: The Acute AQLQ contains the symptom and emotional function items of the AQLQ (n = 11), which are capable of changing over short periods of time. The measurement properties were tested during a clinical trial to compare formoterol and salbutamol in the treatment of acute severe asthma in hospital emergency departments. RESULTS: The 88 patients in the clinical trial provided evidence that the Acute AQLQ has high internal consistency (Cronbach alpha = 0.90) and is very responsive to change in status (p < 0.00001) with a responsiveness index of 2.5. Correlations between the Acute AQLQ and other measures of clinical status provided evidence of the validity of the instrument. CONCLUSION: The Acute AQLQ has strong measurement properties and can be used with confidence to identify the problems that are distressing to patients during an acute asthma exacerbation and to evaluate the effectiveness of interventions.

Clinicians tend to overestimate improvements in asthma control: an unexpected observation.

AIM: The original purpose of this study was to determine the Minimal Important Difference for the Asthma Control Questionnaire (ACQ) but an unexpected tendency of clinicians to overestimate improvements in asthma control thwarted the endeavour. We describe the observed clinician bias and discuss its implications for clinical practice and research. METHODS: Ninety-four adults with inadequately controlled asthma received a full clinical consultation with one of nine asthma specialists. Medications were adjusted according to clinical needs. Four weeks later the same clinician estimated change in asthma control on a 15-point scale (-7 = a very great deal worse, 0 = no change, +7 a very great deal better). All patients completed the ACQ before each consultation but responses were not shown to the clinician. RESULTS: Clinicians consistently recorded that patients improved more than their change in ACQ scores suggested (p = 0.018). CONCLUSION: Clinicians should be aware of potential biases that may occur when estimating change in asthma control compared with measuring absolute status at each visit.

Factors affecting adherence to asthma treatment: patient and physician perspectives.

AIMS: To identify important factors affecting treatment adherence of patients with asthma and to summarise this information as a guide for physicians. METHODS: Information from literature and interviews with 12 respiratory physicians (four each from France, Spain and UK) and 46 asthma patients was obtained. Factors affecting adherence to asthma treatment were identified, reviewed and a flow chart developed to indicate the relationship between key factors. RESULTS: Major factors influencing adherence included: the patient-physician relationship; the patient's understanding of the disease and its treatment; the patient's beliefs and perception of the disease and its treatment, and, importantly, the patient's willingness to take an active part in his/her asthma management. CONCLUSION: Patient adherence to asthma can be improved, and the likelihood of treatment success increased, by paying attention to the factors that influence patients' willingness to participate in their treatment.