Treatment response in COPD: does FEV1 say it all? A post hoc analysis of the CRYSTAL study.

The association between clinically relevant changes in patient-reported outcomes (PROs) and forced expiratory volume in 1 s (FEV1) in patients with chronic obstructive pulmonary disease (COPD) has rarely been investigated. Using CRYSTAL, a 12-week open-label study in symptomatic, nonfrequently exacerbating patients with moderate COPD, we assessed at baseline the correlations between several PROs (Baseline Dyspnoea Index, modified Medical Research Council dyspnoea scale, COPD Assessment Test (CAT) and Clinical COPD Questionnaire (CCQ)), and between FEV1 and PROs. Associations between clinically relevant responses in FEV1, CAT, CCQ and Transition Dyspnoea Index (TDI) at week 12 were also assessed. Using data from 4324 patients, a strong correlation was observed between CAT and CCQ (rs=0.793) at baseline, with moderate or weak correlations between other PROs, and no correlation between FEV1 and any PRO. At week 12, 2774 (64.2%) patients were responders regarding TDI, CAT or CCQ, with 583 (13.5%) responding using all three measures. In comparison, 3235 (74.8%) were responders regarding FEV1, TDI, CAT or CCQ, with 307 (7.1%) responding concerning all four parameters. Increases in lung function were accompanied by clinically relevant improvements of PROs in a minority of patients. Our results also suggest that PROs are not interchangeable. Thus, the observed treatment success in a clinical trial may depend on the selected parameters.

Indacaterol/glycopyrronium reduces the risk of clinically important deterioration after direct switch from baseline therapies in patients with moderate COPD: a post hoc analysis of the CRYSTAL study.

PURPOSE: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 µg (IND/GLY) from previous monotherapy with a long-acting ß2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID. METHODS: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) ≥100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) ≥1 point decrease in transition dyspnea index (TDI) and/or ≥0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334. RESULTS: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]). CONCLUSION: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice.

Effect on Cognition of Estroprogestins Combined with Interferon Beta in Multiple Sclerosis: Analysis of Secondary Outcomes from a Randomised Controlled Trial.

INTRODUCTION: Cognitive impairment is a disabling symptom in multiple sclerosis (MS). While its management remains challenging, beneficial effects on cognition of interferon beta (IFN-ß) have been reported and a positive effect from estroprogestins has been hypothesised, suggesting that the combination of the two medications in women with MS could offer a promising treatment strategy. OBJECTIVES: We investigated whether a combination of estroprogestins and IFN-ß can improve cognition in women with MS. METHODS: Women with relapsing-remitting (RR) MS were randomly assigned (1:1:1) to receive subcutaneous IFN-ß-1a (Rebif®, Merck Serono, Geneva, Switzerland) 44 mcg three times a week (tiw) (group 1), subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 20 mcg and desogestrel 150 mcg (Mercilon®, MSD Italia SRL, Rome, Italy) (group 2) or subcutaneous IFN-ß-1a 44 mcg tiw plus ethinyl estradiol 40 mcg and desogestrel 125 mcg (Gracial®, Organon Italia S.p.A., Rome, Italy) (group 3) in a randomised controlled trial, for which we report the analysis of secondary outcomes. At baseline and at 24 months, all patients underwent magnetic resonance imaging (MRI) and a comprehensive cognitive assessment, including Rao's Brief Repeatable Battery (RBRB) and questionnaires for depression, fatigue and quality of life. Failure in at least two of the RBRB tests defined 'cognitive impairment'. RESULTS: At baseline, there was no difference in the proportion of cognitively impaired patients. At month 24, the proportion of patients with cognitive impairment was lower in group 3 (34.8%) than in group 1 (47.6%) (p = 0.03). The risk of developing cognitive impairment over 24 months was lower in group 3 (p = 0.02). Mood and fatigue scores were comparable across the groups over time at both time points. However, at month 24, group 3 showed worsening on the sexual function subscale of the 54-item MS quality-of-life questionnaire (p = 0.03). CONCLUSIONS: This study suggests that the combination of high-dose estroprogestins and IFN-ß may have positive effects on cognition. However, the effect of this treatment on sexual function requires caution to be exercised. Protocol Number NCT00151801, registered in ClinicalTrials.gov.

Oral contraceptives combined with interferon ß in multiple sclerosis.

OBJECTIVE: To test the effect of oral contraceptives (OCs) in combination with interferon ß (IFN-ß) on disease activity in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: One hundred fifty women with RRMS were randomized in a 1:1:1 ratio to receive IFN-ß-1a subcutaneously (SC) only (group 1), IFN-ß-1a SC plus ethinylstradiol 20 µg and desogestrel 150 µg (group 2), or IFN-ß-1a SC plus ethinylestradiol 40 µg and desogestrel 125 µg (group 3). The primary endpoint was the cumulative number of combined unique active (CUA) lesions on brain MRI at week 96. Secondary endpoints included MRI and clinical and safety measures. RESULTS: The estimated number of cumulative CUA lesions at week 96 was 0.98 (95% confidence interval [CI] 0.81-1.14) in group 1, 0.84 (95% CI 0.66-1.02) in group 2, and 0.72 (95% CI 0.53-0.91) in group 3, with a decrease of 14.1% (p = 0.24) and 26.5% (p = 0.04) when comparing group 1 with groups 2 and 3, respectively. The number of patients with no gadolinium-enhancing lesions was greater in group 3 than in group 1 (p = 0.03). No significant differences were detected in other secondary endpoints. IFN-ß or OC discontinuations were equally distributed across groups. CONCLUSIONS: Our results translate the observations derived from experimental models to patients, supporting the anti-inflammatory effects of OCs with high-dose estrogens, and suggest possible directions for future research. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in women with RRMS, IFN-ß plus ethinylstradiol and desogestrel decreases the cumulative number of active brain MRI lesions compared with IFN-ß alone.