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The Effect of Inhaled Corticosteroid Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study. A Randomized, Double-Blind, Multicenter Clinical Trial.

ABSTRACT: Rationale: In the IMPACT (Informing the Pathway of Chronic Obstructive Pulmonary Disease Treatment) trial, fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) significantly reduced exacerbations compared with FF/VI or UMEC/VI in patients with symptomatic chronic obstructive pulmonary disease and a history of exacerbations.Objectives: To understand whether inhaled corticosteroid (ICS) withdrawal affected IMPACT results, given direct transition from prior maintenance medication to study medication at randomization.Methods: Exacerbations and change from baseline in trough FEV₁ and St. George's Respiratory Questionnaire results were analyzed by prior ICS use. Exacerbations were also analyzed while excluding data from the first 30 days.Measurements and Main Results: FF/UMEC/VI significantly reduced the annual moderate/severe exacerbation rate compared with UMEC/VI in prior ICS users (29% reduction; P < 0.001), but only a numerical reduction was seen among prior ICS nonusers (12% reduction; P = 0.115). To minimize impact from ICS withdrawal, in an analysis excluding the first 30 days, FF/UMEC/VI continued to significantly reduce the annual on-treatment moderate/severe exacerbation rate (19%; P < 0.001) compared with UMEC/VI. The benefit of FF/UMEC/VI compared with UMEC/VI was seen for severe exacerbation rates, regardless of prior ICS use (prior ICS users, 35% reduction; P < 0.001; non-ICS users, 35% reduction; P = 0.018), and overall when excluding the first 30 days (29%; P < 0.001). Improvements from baseline with FF/UMEC/VI compared with UMEC/VI were also maintained throughout the study for both trough FEV₁ and St. George's Respiratory Questionnaire, regardless of prior ICS use.Conclusions: These data support the important treatment effects of FF/UMEC/VI combination therapy on exacerbation reduction, lung function, and quality of life that do not appear to be related to abrupt ICS withdrawal.Clinical trial registered with www.clinicaltrials.gov (NCT02164513).

SUBMITTER: Han MK

PROVIDER: S-EPMC7605201 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeIn the Withdrawal of Inhaled Steroids during Optimized Bronchodilator Management (WISDOM) trial, inhaled corticosteroid (ICS) withdrawal in patients with chronic obstructive pulmonary disease receiving triple therapy (long-acting β2-agonist+long-acting muscarinic antagonist+ICS) did not change moderate/severe exacerbation risk. However, many patients were not taking triple therapy before study participation. This analysis was conducted to eliminate the impact of non-ICS users on WISDOM results by re-analyzing the data using only the subset of patients who were taking triple therapy at screening.Patients and methodsThe effect of ICS withdrawal on moderate/severe exacerbation risk in the subgroup of WISDOM patients taking triple therapy before enrolling in the study was evaluated in this post hoc analysis. Additionally, the effect of ICS withdrawal in patients with a history of ≥2 exacerbations in the previous year and various blood eosinophil counts was assessed.ResultsOverall, 39.0% (n=970: ICS continuation, 479; ICS withdrawal, 491) of the WISDOM trial population were taking triple therapy at screening. Baseline characteristics were generally similar between groups. Moderate/severe exacerbation risk between the ICS withdrawal and continuation groups (hazard ratio [HR], 1.05; 95% confidence interval [CI]: 0.89-1.25) was not increased in patients taking triple therapy at screening versus the overall trial population (HR [95% CI]: 1.06 [0.94-1.19]). However, in patients with a history of ≥2 exacerbations, exacerbation risk (HR [95% CI]) increased nominally with blood eosinophil count from 1.07 [0.81-1.41] (≥100 cells/μL) to 1.45 [0.58-3.60] (≥400 cells/μL).ConclusionConsistent with results from the overall WISDOM trial population, ICS withdrawal did not increase exacerbation risk in patients taking triple therapy at screening. Patients with a history of frequent exacerbations and higher blood eosinophil counts could benefit from continuation of ICS-based therapy.

Project description:Abstract Background: In a Phase II study, osilodrostat, a potent oral 11β-hydroxylase inhibitor, normalized mean urinary free cortisol (mUFC) in most patients with CD (Fleseriu M et al. Pituitary 2016;19:138-48). We report the efficacy and safety of osilodrostat in a large CD patient population in the first randomized withdrawal Phase III study in this rare, serious disorder (clinicaltrials.gov: NCT02180217). Methods: Phase III, multicenter, double-blind, randomized withdrawal study following a 24-week, open-label, single-arm treatment phase. Open-label osilodrostat was initiated at 2 mg bid in 137 adults with CD and mUFC (mean of three 24-h samples) >1.5xULN (ULN=50.0 µg/24h), with dose adjustments every 2 weeks (dose range 1-30 mg bid) up to week (W) 12 based on efficacy (if mUFC >ULN) and tolerability. At W26, 71 eligible patients (mUFC ≤ULN at W24 without a dose increase after W12) were randomized to continue osilodrostat (n=36) or matching placebo (n=35) for 8 weeks, followed by open-label osilodrostat until W48. Patients who remained on treatment at W26 but were not eligible for randomization continued open-label osilodrostat (n=47). Primary endpoint: patients in each randomized group with mUFC ≤ULN at the end of the randomized withdrawal phase (W34) without a dose increase after W26. For all mUFC assessments, patients who discontinued were classed as non-responders at subsequent time points. Results: At baseline, median (range) mUFC was 3.5xULN (0.3-69.6) in enrolled patients. At the end of the randomized withdrawal period (W34), significantly more patients maintained mUFC ≤ULN (without a dose increase after W26) in the osilodrostat group than in the placebo group (86% vs 29%; OR 13.7, P<0.001). Other endpoints: at W24, 53% of enrolled patients had mUFC ≤ULN without a dose increase after W12 (key secondary endpoint); at W48, 66% of enrolled patients had mUFC ≤ULN; 96% of enrolled patients had mUFC ≤ULN at least once during the study; median time to first mUFC ≤ULN was 41 days. Median (range) duration of osilodrostat exposure was 75 weeks (1-165). By W48, 24 (18%) patients had discontinued the study, 15 (11%) because of AEs. Overall, the most common AEs were nausea (42%), headache (34%) and fatigue (28%). AEs related to hypocortisolism and adrenal-hormone-precursor accumulation occurred in 51% and 42% of patients, respectively. The most common AEs reported in the osilodrostat group during the randomized withdrawal period were nausea (11% vs 0% for placebo), anemia (8% vs 9%), arthralgia (8% vs 0%) and headache (8% vs 0%). Conclusion: Osilodrostat was significantly superior to placebo at maintaining mUFC ≤ULN after randomized withdrawal and normalized mUFC in two-thirds of enrolled patients at W48, with few patients discontinuing treatment because of AEs. This randomized withdrawal study demonstrates osilodrostat to be a highly effective treatment for CD, with good tolerability.

Project description:BackgroundGlycyrrhizin is widely used in skin disorders, such as psoriasis, alopecia areata, and allergic diseases, but has not been extensively studied in patients with chronic eczema.ObjectiveTo evaluate the efficacy and safety of oral compound glycyrrhizin (OCG) plus topical corticosteroid (TCS) in adults with chronic eczema.MethodsThis was a multicenter, randomized, double-blind, placebo-controlled study in patients with chronic eczema (n = 199). Randomized participants from 6 centers in China received either 75 mg OCG capsules or placebo capsules three times a day and TCS (i.e., 0.1% mometasone furoate ointment) once a day for 28 days. Efficacy was determined by analyzing the mean change from the baseline using standardized measures including the Investigator's Global Assessment (IGA) score, Eczema Area and Severity Index (EASI), and the visual analogue scale score (VAS) of itching.ResultsDecreases in absolute EASI were significantly greater in the OCG-treated group versus placebo on day 14 (-3.41 ± 1.41 vs. -2.71 ± 1.25, P < 0.001) and day 28 (-7.39 ± 1.71 vs. -6.64 ± 1.75, P=0.003). OCG-treated patients also saw greater benefit in other EASI metrics including EASI-50 (96.8% vs. 87.9%, P=0.021) and EASI-75 (47.9% vs. 21.2%, P < 0.001) on day 28 compared with placebo. The absolute IGA score reductions were also significantly greater in the OCG group than the placebo (all P < 0.05). In addition, proportions of patients who achieve clear (0) IGA scores or almost clear (1) IGA scores were significantly higher in the treated group than placebo on day 14 (22.8% vs. 6.2%, P=0.001) and day 28 (93.5% vs. 79.4%, P=0.005). Moreover, the proportions of patients with reduced pruritus were significantly greater in the treated group than placebo on day 28 (94.7% vs. 83.8%, P=0.016) and eczema recurrence was notably less in the OCG group versus placebo (3.19% vs. 12.12%, P=0.021). Eleven patients experienced adverse events, but there was no significant difference in the proportion of patients affected (3.0% vs. 8.5%, P > 0.05). The most common adverse events were edema of both lower limbs.ConclusionFor adults with chronic eczema, OCG capsules combined with TCS is an effective and well-tolerated treatment, suggesting that OCG may be a useful nonsteroidal agent with an additional effect for the treatment of chronic eczema by TCS.

Dataset Information

The Effect of Inhaled Corticosteroid Withdrawal and Baseline Inhaled Treatment on Exacerbations in the IMPACT Study. A Randomized, Double-Blind, Multicenter Clinical Trial.

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