Early Changes in eDiary COPD Symptoms Predict Clinically Relevant Treatment Response at 12 Weeks: Analysis from the CRYSTAL Study.

Early detection of treatment response is important in the long-term treatment and management of patients with chronic obstructive pulmonary disease (COPD). This analysis evaluated whether early improvement in symptoms, recorded in the first 7 or 14 days via an electronic diary (eDiary) compared with baseline, can predict clinically meaningful treatment responders at 12 weeks. CRYSTAL was a 12-week, randomized, open-label study that demonstrated the increased effectiveness of indacaterol/glycopyrronium (IND/GLY) or glycopyrronium (GLY), after a direct switch from on-going baseline therapies, in patients with symptomatic COPD and moderate airflow obstruction. The co-primary endpoints were trough forced expiratory volume in 1 second (FEV1) and transition dyspnea index (TDI) at Week 12. Patients' symptom status was recorded daily in an eDiary. Of 4,389 patients randomized, 3,936 and 3,855 reported symptoms on Days 7 and 14, respectively. Patients who reported an early decrease in symptoms on Day 7 or 14 were more likely to achieve the minimal clinically important difference of ≥100 mL in trough FEV1 or ≥ 1 point in TDI at Week 12. Using stepwise multivariate regression models we identified as best predictors of FEV1 responders the decrease in wheeze on Day 7, and nighttime symptoms and wheeze on Day 14; best predictors of TDI responders were decrease in nighttime symptoms and wheeze on Day 7, and nighttime symptoms, sputum and wheeze on Day 14. Early symptom improvement at Day 7 or 14, especially wheeze and nighttime symptoms, may identify patients with clinically important improvement in lung function and dyspnea at Week 12.

Efficacy and safety of direct switch to indacaterol/glycopyrronium in patients with moderate COPD: the CRYSTAL open-label randomised trial.

BACKGROUND: Dual bronchodilation combining a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) is the preferred choice of treatment recommended by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2017 guidelines for the management of patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). The once-daily (q.d.) fixed-dose combination (FDC) of LABA, indacaterol 110 µg and LAMA, glycopyrronium 50 µg (IND/GLY 110/50 µg q.d.) demonstrated superior improvements in lung function, dyspnoea and overall health status and better tolerability against LABA or LAMA monotherapies and combination of LABA and inhaled corticosteroid (ICS) in more than 11,000 patients with moderate-to-severe COPD in several randomised controlled clinical trials. METHODS: The CRYSTAL study was the first, 12-week, randomised, open-label trial that evaluated the efficacy and safety of a direct switch from previous treatments to IND/GLY 110/50 µg q.d. on lung function and dyspnoea in patients with moderate COPD and a history of up to one exacerbation in the previous year. Patients were divided into 2 groups according to their background therapy and symptom scores and were randomised (3:1) to IND/GLY or to continue with their previous treatments. RESULTS: The study included 4389 randomised patients, of whom 2160 were in groups switched to IND/GLY (intention-to-treat population). The effect of IND/GLY was superior to LABA + ICS on trough forced expiratory volume in 1 s (FEV1; treatment difference, Δ = +71 mL) and transition dyspnoea index (TDI; [Δ = 1.09 units]), and to LABA or LAMA on trough FEV1 (Δ = +101 mL) and a TDI (Δ = 1.26 units). Improvements in health status and lower rescue medication use were also observed with IND/GLY. The safety profile of the study medication was similar to that observed in previous studies. CONCLUSIONS: IND/GLY demonstrated superior improvements in lung function and dyspnoea after direct switch from previous treatments. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01985334 .

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.

Effects of diazoxide in multiple sclerosis: A randomized, double-blind phase 2 clinical trial.

OBJECTIVE: The aim of this study was to test the safety of diazoxide and to search for signs of efficacy in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: In this multicenter, randomized, placebo-controlled, double-blind trial (treatment allocation was concealed), 102 patients with RRMS were randomized to receive a daily oral dose of diazoxide (0.3 and 4 mg/d) or placebo for 24 weeks (NCT01428726). The primary endpoint was the cumulative number of new T1 gadolinium-enhancing lesions per patient, recorded every 4 weeks from week 4 to week 24. Secondary endpoints included brain MRI variables such as the number of new/enlarging T2 lesions and the percentage brain volume change (PBVC); clinical variables such as the percentage of relapse-free patients, relapse rate, and change in the Expanded Disability Status Scale score; and safety and tolerability. RESULTS: Diazoxide was well-tolerated and it produced no serious adverse events other than 1 case of Hashimoto disease. At the 2 doses tested, diazoxide did not improve the primary endpoint or the MRI and clinical variables related to the presence of new lesions or relapses. Patients treated with diazoxide showed reduced PBVC compared with the placebo group, although such changes could be confounded by the higher disease activity of the treated group and the vascular effects of diazoxide. CONCLUSION: At the doses tested, oral diazoxide did not decrease the appearance of new lesions evident by MRI. The effects in slowing the progression of brain atrophy require further validation. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RRMS, diazoxide (0.3 and 4 mg/d) does not significantly change the number of new MRI T1 gadolinium-enhancing lesions.