Measurement properties of the Haem-A-QoL in haemophilia clinical trials.

INTRODUCTION: Patients with haemophilia on long-acting prophylactic treatment may experience an improvement in health-related quality of life (HRQoL) through reductions in breakthrough bleeds and associated complications, including long-term joint damage, compared with episodic treatment. AIM: This analysis examined clinical trial data to understand the psychometric characteristics (reliability, validity and sensitivity to change over time) of the Haem-A-QoL Questionnaire in adult males with haemophilia. METHODS: Two recent, multinational, Phase 3 clinical trials of new, long-acting factor concentrates (A-LONG: rFVIIIFc; B-LONG: rFIXFc) assessed HRQoL in adolescent and adult males with severe haemophilia A or B respectively. The adults' baseline assessments, via the 46-item Haem-A-QoL Questionnaire, and change over time at the 6-month assessment were used in the psychometric analyses. RESULTS: Internal consistency reliability was adequate (Cronbach's alpha > 0.70) for nine of the 10 Haem-A-QoL domains and for 'Total Score' in both trials at baseline (A-LONG, n = 133; B-LONG, n = 73). At baseline, several Haem-A-QoL domains and 'Total Score' demonstrated known-groups and convergent validity when compared with other trial measures, including the EQ-5D (items and total scores) and joint impairment. Change score correlations (baseline to 28 weeks) between the EQ-5D and the Haem-A-QoL 'Total Score', and 'Physical Health' and 'Feelings' domains were moderate in magnitude (│r│ ≥ 0.33; P < 0.03), demonstrating sensitivity to change for these outcome measures in A-LONG. CONCLUSION: These psychometric analyses provide evidence of the reliability, validity and ability to detect change of the Haem-A-QoL to assess the HRQoL of adult males with severe haemophilia A and B in longitudinal clinical trials.

Changes in health-related quality of life with treatment of longer-acting clotting factors: results in the A-LONG and B-LONG clinical studies.

INTRODUCTION: In haemophilia, prophylactic infusion of replacement factor can result in improvements in health-related quality of life (HRQoL) when compared with episodic treatment. The Haemophilia-specific Quality of Life (Haem-A-QoL) questionnaire assessed HRQoL in adults with severe haemophilia A or B who received prophylactic or episodic treatment with recombinant factor VIII or IX Fc fusion protein (rFVIIIFc or rFIXFc) in the A-LONG or B-LONG clinical studies. AIMS: Understand changes in HRQoL during the A-LONG and B-LONG trials. METHODS: Group-level and individual-level changes over time for the Haem-A-QoL key domains of 'Physical Health' and 'Sports & Leisure,' and 'Total Score' were evaluated in adults through baseline and 6-month HRQoL assessments. Previously determined responder definitions (RDs) were used for evaluating meaningful subject-level HRQoL improvements. RESULTS: The analysis included 67 A-LONG and 51 B-LONG subjects who completed the Haem-A-QoL (baseline and 6 months). While HRQoL improvements were observed among all treatment groups, greater improvements in HRQoL were observed among subjects who received episodic treatment pre-study (and prophylaxis on-study) compared to those who received hyphenate prophylaxis. Applying the RDs for interpreting 6-month changes, 47.4%/33.3% ('Physical Health'), 35.9%/50.0% ('Sports & Leisure') and 23.9%/33.3% ('Total Score') of A-LONG subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. In B-LONG, 69.2%/57.9% ('Physical Health'), 44.4%/56.7% ('Sports & Leisure') and 41.7%/44.1% ('Total Score') of subjects who received individualized or weekly prophylaxis were classified as HRQoL responders. CONCLUSION: Changes in Haem-A-QoL key domains and 'Total Score' suggest that prophylaxis with long-acting rFVIIIFc or rFIXFc resulted in meaningful HRQoL improvements.

Interpreting important health-related quality of life change using the Haem-A-QoL.

The Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QoL) measures health-related quality of life (HRQoL) in adults with haemophilia; however, change score thresholds for identifying individuals experiencing a HRQoL benefit have not been appropriately investigated. The objective of this analysis was to derive appropriate HRQoL responder definitions (RDs) for two Haem-A-QoL domains that reflect key impairments, 'Physical Health' and 'Sports & Leisure,' and the Haem-A-QoL 'Total Score' using anchor- and distribution-based methods. In this analysis, data from adults in A-LONG and B-LONG, two Phase 3 clinical studies of rFVIIIFc in haemophilia A and rFIXFc in haemophilia B, respectively, were used. The anchor-based approach identified Haem-A-QoL changes corresponding to EQ-5D item improvements between baseline and 6 months; the distribution-based methods examined the magnitude at baseline of one-half standard deviation and the standard error of measurement. Through triangulation, the most appropriate RDs were derived. Of the 133 A-LONG and 73 B-LONG subjects with baseline Haem-A-QoL scores, 67 and 51 subjects, respectively, completed the Haem-A-QoL questionnaire at both baseline and 6 months follow-up. Triangulation of anchor- and distribution-based estimates with the observed Haem-A-QoL change scores identified a 10-point reduction in the 'Physical Health' and 'Sports & Leisure' domains, and a 7-point reduction in 'Total Score' as the RD thresholds most indicative of HRQoL benefit. These empirically derived RDs for two key Haem-A-QoL domains and 'Total Score' are reasonable and practical thresholds for identifying subjects with notable improvements in HRQoL, and provides HRQoL RDs that can be used for further analysis and interpretation of data from haemophilia clinical trials.

Budesonide/formoterol for maintenance and reliever therapy of asthma: a meta analysis of randomised controlled trials.

OBJECTIVES: To compare the effectiveness of budesonide/formoterol (Symbicort) for Maintenance and Reliever Therapy (Symbicort SMART) Turbuhaler with twice daily inhaled corticosteroid (ICS) treatment, alone or in combination with a long-acting beta(2)-agonist (LABA). METHODS: Meta analysis of randomised controlled trials (RCTs) using a fixed effects model. RCTs were included if the comparator with budesonide/formoterol for maintenance and relief had the equivalent, or up to fourfold higher, maintenance dose of ICS. The primary outcome was the incidence of severe exacerbation (oral glucocorticosteroid treatment for > or = 3 days, emergency visit and/or hospitalisation). RESULTS: Of the seven RCTs available six met the inclusion criteria. Risk of severe exacerbations was significantly reduced: 41% vs. higher-dose budesonide alone [relative risk (RR) 0.59, 95% confidence interval (95% CI): 0.51-0.68, p < 0.00001]; 43% vs. equivalent dose budesonide/formoterol as maintenance twice daily (RR 0.57, 95% CI: 0.49-0.66, p < 0.00001); 24% vs. higher-dose salmeterol/fluticasone twice daily (RR 0.76, 95% CI: 0.64-0.90, p = 0.002); and 26% vs. higher-dose budesonide/formoterol twice daily (RR 0.74, 95% CI: 0.58-0.96, p = 0.02). Significant heterogeneity was not detected in the primary analyses (p > 0.1). Secondary analyses also demonstrated that budesonide/formoterol for maintenance and relief reduced the most severe exacerbations, resulting in less hospitalisations/accident and emergency visits than higher-dose budesonide, equivalent dose budesonide/formoterol and higher-dose salmeterol/fluticasone twice daily. CONCLUSION: Budesonide/formoterol for maintenance and relief is significantly more effective at reducing severe exacerbations than higher-dose ICS alone, or in combination with a LABA. This has important implications for treating uncontrolled patients at steps 2 and 3 of the joint BTS/SIGN guidelines.