Efficacy and Safety of Vamorolone Over 48 Weeks in Boys With Duchenne Muscular Dystrophy: A Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Vamorolone is a dissociative agonist of the glucocorticoid receptor that has shown similar efficacy and reduced safety concerns in comparison with prednisone in Duchenne muscular dystrophy (DMD). This study was conducted to determine the efficacy and safety of vamorolone over 48 weeks and to study crossover participants (prednisone to vamorolone; placebo to vamorolone). METHODS: A randomized, double-blind, placebo-controlled and prednisone-controlled clinical trial of 2 doses of vamorolone was conducted in participants with DMD, in the ages from 4 years to younger than 7 years at baseline. The interventions were 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks) and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover). Efficacy was evaluated through gross motor outcomes and safety through adverse events, growth velocity, body mass index (BMI), and bone turnover biomarkers. This analysis focused on period 2. RESULTS: A total of 121 participants with DMD were randomized. Vamorolone at a dose of 6 mg/kg/d showed maintenance of improvement for all motor outcomes to week 48 (e.g., for primary outcome, time to stand from supine [TTSTAND] velocity, week 24 least squares mean [LSM] [SE] 0.052 [0.0130] rises/s vs week 48 LSM [SE] 0.0446 [0.0138]). After 48 weeks, vamorolone at a dose of 2 mg/kg/d showed similar improvements as 6 mg/kg/d for North Star Ambulatory Assessment (NSAA) (vamorolone 6 mg/kg/d-vamorolone 2 mg/kg/d LSM [SE] 0.49 [1.14]; 95% CI -1.80 to 2.78, p = 0.67), but less improvement for other motor outcomes. The placebo to vamorolone 6 mg/kg/d group showed rapid improvements after 20 weeks of treatment approaching benefit seen with 48-week 6 mg/kg/d of vamorolone treatment for TTSTAND, time to run/walk 10 m, and NSAA. There was significant improvement in linear growth after crossover in the prednisone to vamorolone 6 mg/kg/d group, and rapid reversal of prednisone-induced decline in bone turnover biomarkers in both crossover groups. There was an increase in BMI after 24 weeks of treatment that then stabilized for both vamorolone groups. DISCUSSION: Improvements of motor outcomes seen with 6 mg/kg/d of vamorolone at 24 weeks of treatment were maintained to 48 weeks of treatment. Vamorolone at a dose of 6 mg/kg/d showed better maintenance of effect compared with vamorolone at a dose of 2 mg/kg/d for most (3/5) motor outcomes. Bone morbidities of prednisone (stunting of growth and declines in serum bone biomarkers) were reversed when treatment transitioned to vamorolone. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03439670. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for boys with DMD, the efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks.

Oral mometasone furoate administration preserves anti-inflammatory action with fewer metabolic adverse effects in rats.

BACKGROUND: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism. METHODS: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control. RESULTS: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic ß-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible. CONCLUSION: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology.

Quail egg homogenate with zinc as adjunctive therapy in seasonal allergic rhinitis: a randomised, controlled trial.

OBJECTIVE: Because most available treatments for managing seasonal allergic rhinitis show some side effects without reducing recurrence, natural anti-allergic products could represent an interesting treatment addition. This study aimed to analyse the efficacy and tolerance of quail egg as adjunctive therapy in seasonal allergic rhinitis. METHOD: In a Consolidated Standards of Reporting Trials compliant framework, patients with seasonal allergic rhinitis were prospectively randomised to receive mometasone nasal spray for four weeks or the same topical corticosteroid therapy plus commercially available oral quail egg and zinc tablets. RESULTS: Forty patients were enrolled. The mometasone + quail egg and zinc tablets group showed a greater reduction in nasal itching, sneezing and total nasal symptom scores than the mometasone nasal spray only group. A higher proportion of participants in the mometasone + quail egg and zinc tablets group had good rhinitis control than in the mometasone nasal spray only group, with no need for rescue medications. CONCLUSION: Despite the need for a further larger study, quail egg preliminarily appears to be an effective adjunct to topical steroid therapy in seasonal allergic rhinitis.

Pharmacokinetic Evidence of Steady and Sustained Drug Release from Long-Acting Implantable Corticosteroid Matrices for Chronic Rhinosinusitis.

BACKGROUND: The efficacy of topical corticosteroids is limited in chronic rhinosinusitis (CRS) due to rapid clearance from the nasal cavity and insufficient drug delivery to inflamed sinonasal passages. LYR-210 is an implantable corticosteroid matrix designed to provide up to 24 weeks of treatment to patients with CRS by locally delivering mometasone furoate (MF) to the sinonasal mucosa. In a randomized, controlled, dose-ranging LANTERN study, LYR-210 (7500 µg) achieved clinically relevant improvement in CRS cardinal symptom composite scores, the 22-item Sinonasal Outcome Test (SNOT-22), ethmoid opacification, and the need for rescue treatment at 24 weeks. OBJECTIVE: As the plasma MF concentrations of LYR-210 (2500 µg) and LYR-210 (7500 µg) were evaluated at weeks 4, 12, and 24 in the LANTERN study (data on file at Lyra Therapeutics, Inc.), this study aims to characterize the pharmacokinetic profiles of both doses of LYR-210 at earlier timepoints post-placement in patients with CRS. METHODS: Twenty-four surgically naïve adult patients with CRS were enrolled in an open-label, multicenter study and underwent in-office bilateral administration of LYR-210 (2500 µg) (n = 12 patients) or LYR-210 (7500 µg) (n = 12 patients) into the middle meatus. Plasma MF concentrations were determined pre-placement and 1-h post-placement (day 1), and on days 2, 3, 7, 14, 21, 28, 42, and 56 by liquid chromatography-tandem mass spectrometry. RESULTS: Both LYR-210 doses were well-tolerated with no serious adverse events. Systemic MF levels were dose-dependent and lower than reported values of other respiratory MF products. Plasma MF concentrations showed steady drug release from LYR-210 (2500 µg) and LYR-210 (7500 µg) that persisted through day 56. CONCLUSION: LYR-210 achieved dose-dependent, continuous local MF delivery at a steady rate with low systemic exposure for months.

Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy.

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax ), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50  = 186 ng·h/mL), followed by time to climb 4 stairs (E50  = 478 ng·h/mL), time to run/walk 10 m (E50  = 1220 ng·h/mL), and 6-minute walk test (E50  = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/ß2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice.

Clinicians often hesitate prescribing corticosteroids to treat corticosteroid-responsive conditions in sickle cell disease (SCD) patients because their use can be associated with complications (increased hospital readmission, rebound pain, strokes, avascular necrosis, acute chest syndrome). Consequently, SCD patients may receive suboptimal treatment for corticosteroid-responsive conditions. We conducted a preclinical trial of dissociative (vamorolone) and conventional (prednisolone) corticosteroid compounds to evaluate their effects on nociception phenotype, inflammation, and organ dysfunction in SCD mice. Prednisolone and vamorolone had no significant effects on nociception phenotype or anemia in homozygous mice. Conversely, prednisolone and vamorolone significantly decreased white blood cell counts and hepatic inflammation. Interestingly, the effects of vamorolone were milder than those of prednisolone, as vamorolone yielded less attenuation of hepatic inflammation compared to prednisolone. Compared to controls and heterozygotes, homozygotes had significant liver necrosis, which was significantly exacerbated by prednisolone and vamorolone despite decreased hepatic inflammation. These hepatic histopathologic changes were associated with increases in transaminases and alkaline phosphatase. Together, these results suggest that, even in the setting of decreasing hepatic inflammation, prednisolone and vamorolone were associated with significant hepatic toxicity in SCD mice. These findings raise the possibility that hepatic function deterioration could occur with the use of corticosteroids (conventional and dissociative) in SCD.

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes.

BACKGROUND: Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. PURPOSE: Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. EXPERIMENTAL APPROACH: We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1-20.0 mg/kg), and multiple ascending doses (1.0-20 mg/kg/day; 14 days treatment). KEY RESULTS: Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. CONCLUSIONS AND INTERPRETATIONS: Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

Lung Delivery of Indacaterol and Mometasone Furoate Following Inhalation of QMF149 in Healthy Volunteers.

This single-dose, 4-period crossover study evaluated the pharmacokinetics (PK) of the ß2 -agonist indacaterol maleate and the corticosteroid mometasone furoate (MF) after inhalation of a fixed-dose combination (QMF149, indacaterol maleate/MF, 500/400 µg) via the Twisthaler (TH) device with and without activated charcoal and postdose mouth rinsing in healthy volunteers. The PK of indacaterol maleate 300 µg inhaled via the Breezhaler (BRZ) device was also characterized. Relative bioavailability of indacaterol and MF for inhalation with versus without charcoal, based on AUClast, was 0.25 (90% confidence interval [CI], 0.18-0.35) and 0.70 (90%CI, 0.52-0.93), respectively. Thus, 25% and 70% of systemic exposure of indacaterol and MF, respectively was due to pulmonary absorption and 75% and 30%, respectively, was due to gastrointestinal absorption. Mouth rinsing reduced the systemic exposure of indacaterol by approximately 35% but had no relevant effect on the exposure of MF. Dose-normalized AUClast for indacaterol inhaled via the BRZ device was 2.3-fold higher than QMF149 via the TH device. All treatments had a good safety profile and were well tolerated. Data from this study and comparison with inhalation of indacaterol via the BRZ device suggest that the latter was more efficient than the TH device regarding lung delivery of indacaterol.

Pharmacokinetics of QMF149 in Japanese versus Caucasian subjects: an open-label, randomized phase I study.

OBJECTIVES: This study aimed to evaluate influence of ethnic factors on the pharmacokinetics of orally inhaled QMF149, a novel combination of an approved longacting ß2-agonist, indacaterol (Onbrez® Breezhaler® for COPD), and an approved inhaled corticosteroid, mometasone furoate (MF), (Asmanex® Twisthaler® for asthma), following multiple dose administration of QMF149 (indacaterol acetate/MF) 150/80 µg and 150/320 µg via the Breezhaler® device in healthy Japanese and Caucasian subjects. METHODS: This was a single-center, openlabel, multiple-dose, two-period, complete crossover study that randomized healthy Japanese and, age and weight matched Caucasian subjects to QMF149 150/80 µg or 150/320 µg once daily (o.d.) for 14 days in each period. Pharmacokinetics (PK) were assessed up to 24 hours on days 1 and 14. RESULTS: 24 Japanese and 24 Caucasian healthy subjects were enrolled. Indacaterol and MF had similar PK profiles across both the doses and both ethnic groups. The maximum geometric mean ratios (90% confidence interval (CI)) for Japanese vs. Caucasian subjects for Cmax were 1.23 (1.11 - 1.38) and 1.24 (1.11 - 1.38) for indacaterol and MF, respectively. For AUC, the maximum ratios were 1.22 (1.09 - 1.36) and 1.30 (1.18 - 1.44) for indacaterol and MF, respectively. The mild trend towards higher exposure in Japanese subjects could be explained by the fact that the mean body weight was 14% higher for Caucasians compared to their Japanese counterparts. No serious adverse events or discontinuations related to study medication were reported. CONCLUSION: The study demonstrated increase of mean exposure parameters in Japanese subjects vs. Caucasian subjects, which ranged between 19 - 23% and 17 - 30%, for indacaterol and MF components, respectively. Multiple doses of both the QMF149 dose levels were safe and well-tolerated in all subjects. Body weight was considered a key contributory factor for the observed difference in exposure. These results suggest no dose adjustment for QMF149 is required in Asian populations.

Regional deposition of mometasone furoate nasal spray suspension in humans.

Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.

Comparing the efficacy and safety of salmeterol/fluticasone pMDI versus its mono-components, other LABA/ICS pMDIs and salmeterol/fluticasone Diskus in patients with asthma.

INTRODUCTION: Pressurized metered dose inhalers (pMDIs) are evolving to be a very effective drug delivery option in patients with airway diseases. They offer comparable lung deposition and reduced oropharyngeal deposition similar with the dry powder inhalers. As recommended by the Global Initiative for Asthma guidelines, the ideal maintenance treatment for asthma is a combination of long acting ß2-agonists (LABAs) and inhaled corticosteroids (ICSs). One of the available LABA/ICS combinations is the salmeterol/fluticasone propionate combination (SFC) and a plethora of evidence supports its clinical efficacy and safety. AREAS COVERED: This article focuses on the SFC hydrofluroalkane pMDI and compares the efficacy and tolerability with salmeterol and fluticasone given individually, and with other fixed-dose combinations namely formoterol/fluticasone, formoterol/beclometasone and formoterol/mometasone furoate, all delivered via pMDI. Also discussed is the efficacy and tolerability of the SFC delivered via a pMDI, as compared to the SFC via Diskus. EXPERT OPINION: pMDIs play an important role in inhalation therapy given the low price, low maintenance and convenience of use. LABA/ICS combinations are the preferred choice of medication for asthma treatment and will remain the mainstay for the decades to come. In our opinion, pMDI should be the choice of device to administer LABA/ICS maintenance therapy, as it is already being used by the patients for reliever therapy, which may eventually improve patient adherence and compliance.

The influence of mometasone furoate ear solution on intradermal test immediate reactions in dogs with atopic dermatitis.

BACKGROUND: Topical ear medications, often containing a glucocorticoid, are used to treat the clinical signs of atopic otitis in dogs. Studies have looked at the inhibitory effect of topical glucocorticoids on intradermal testing (IDT), but only one previously published study evaluated the influence of an otic glucocorticoid on the results of IDT in dogs. HYPOTHESIS/OBJECTIVES: To assess what influence the absorption of the diester glucocorticoid mometasone furoate (MF) had on intradermal test immediate reactions, to determine an appropriate withdrawal time prior to IDT. METHODS: Twenty atopic dogs were enrolled. On day 0, histamine, rabbit anticanine IgE antiserum and saline were injected intradermally. After 20 min, a global wheal score (GWS) was determined. The otic medication, MF, was applied once daily for 14 days. Intradermal injections were then repeated and, if the GWS was within 25% of pretreatment values, the study was completed for this dog. If the GWS had decreased by ≥25% from the baseline value, the otic medication was withdrawn, and the GWS was repeated every 7 days until its value was within 25% of the original GWS. RESULTS: Three of the 20 dogs completed the study on day 14, while 17 of 20 dogs ended it on day 21, 7 days after withdrawal of the drug, MF. CONCLUSIONS AND CLINICAL IMPORTANCE: Results from this study show that a withdrawal period of ≤7 days is possible before performing IDT in atopic dogs with active otitis externa treated with ≤14 days of MF.

Appraisal of lens opacity with mometasone furoate/formoterol fumarate combination in patients with COPD or asthma.

BACKGROUND: Long-term corticosteroid use may increase cataract risk. The Lens Opacities Classification System (LOCS) III ranked lens opacities as Class 1: 0.5-0.9 unit; Class 2: 1.0-1.4 units; or Class 3: ≥1.5 units in clinical trials of combined mometasone furoate and formoterol (MF/F) administered by metered-dose inhaler (MDI). We examined retrospectively shifts in lenticular opacity in patients with chronic obstructive pulmonary disease (COPD) or asthma. METHODS: We analyzed pooled LOCS III data from two COPD studies and separately analyzed LOCS III data from an asthma study. COPD subjects were randomized to twice daily MF/F 200/10 µg, MF/F 400/10 µg, MF 400 µg, F 10 µg, and placebo; asthma subjects were randomized to MF/F 200/10 µg, MF/F 400/10 µg, fluticasone propionate/salmeterol (FP/S) 250/50 µg, and FP/S 500/50 µg. Lenticular opacity changes were analyzed post hoc for proportions of subjects with LOCS III grade increases ≥0.5, ≥1.0, or ≥1.5 units at weeks 26 and 52. RESULTS: Proportions of subjects in the COPD studies with Class 1 (≥0.5 unit), 2 (≥1.0 unit), or 3 (≥1.5 units) increases in LOCS III at week 26 (N = 1675) ranged from 15.5 to 18.6%, 3.3-6.0%, and 0.9-2.2%, respectively. At week 52 (N = 1085), proportions of active-treated subjects with Class 1, 2, or 3 increases in LOCS III ranged from 26.6 to 28.9%, 6.3-10.7%, and 2.6-5.9%, respectively. Treatment differences in lenticular shifts were generally small and nonsignificant in the asthma study. CONCLUSION: No clinically relevant trends were observed in the LOCS III assessment of lenticular shifts during treatment of COPD and asthma patients, although further study may be needed to confirm the findings presented here. In these trials, MF/F effects on lens opacity were not observed. (Clinicaltrials.gov numbers: NCT00383435, NCT00383721, and NCT00379288.).

Inhaled corticosteroids in children with persistent asthma: effects on growth.

BACKGROUND: Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth. OBJECTIVES: To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment). SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child. MAIN RESULTS: We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 µg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated linear growth velocity in the fluticasone group at 12 months after treatment cessation, but there remained a statistically significant difference of 0.7 cm in height between the fluticasone and placebo groups at the end of the three-year trial.One trial with follow-up into adulthood showed that participants of prepubertal age treated with budesonide 400 µg/d for a mean duration of 4.3 years had a mean reduction of 1.20 cm (95% CI -1.90 to -0.50) in adult height compared with those treated with placebo. AUTHORS' CONCLUSIONS: Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Inhaled corticosteroids in children with persistent asthma: dose-response effects on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians. OBJECTIVES: To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014. SELECTION CRITERIA: Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation. MAIN RESULTS: Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 µg) versus low to medium (200 µg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision. AUTHORS' CONCLUSIONS: In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

Comparative safety and efficacy of two formulations of mometasone nasal spray in adult seasonal allergic rhinitis.

Mometasone furoate as a nasal spray is an effective treatment for seasonal allergic rhinitis (SAR). An aqueous mometasone nasal spray containing the same active substance and excipients as the originator product (reference mometasone) has been developed. This study was designed to establish therapeutic equivalence of test mometasone to reference mometasone and superiority over placebo for the treatment of SAR in adults. In this multicenter, randomized, double-blind, placebo- and active-controlled, fixed-dose study, patients aged ≥18 years with SAR were randomized 2:2:1 to reference mometasone, test mometasone, or placebo for 28 days. Patients recorded nasal and ocular symptoms daily. The primary end point was change from baseline in the pooled 24-hour reflective total nasal symptom score (rTNSS). Safety and tolerability included evaluation by adverse events (AEs), physical (including nasal) examinations, vital signs assessments, laboratory evaluations, and change in concomitant medications. Four hundred two patients received reference mometasone (n = 156), test mometasone (n = 163), or placebo (n = 83). The intent-to-treat population (ITT) comprised 399 patients, and the per-protocol (PP) population comprised 327 patients. The 95% confidence intervals for the treatment difference (reference minus test mometasone) in change from baseline in pooled 24-hour rTNSS were within prespecified equivalence limits for the PP and ITT populations. Both active treatments showed superiority over placebo (p = 0.0019-0.0087). No significant difference was seen between test mometasone and reference mometasone for any secondary efficacy variables. Treatment-emergent AE incidence was low. No deaths or serious AEs were reported. The test mometasone is efficacious in the treatment of SAR in adults and shows a favorable safety profile. The results indicate that the test mometasone is therapeutically equivalent to the reference mometasone.

Efficacy of long-term low-dose macrolide therapy in preventing early recurrence of nasal polyps after endoscopic sinus surgery.

BACKGROUND: This study assessed efficacy of clarithromycin "long-term" macrolide therapy as an adjunct to maintenance therapy with nasal corticosteroids to prevent recurrence of nasal polyps (NP) after functional endoscopic sinus surgery (FESS). METHODS: A total of 66 patients with chronic rhinosinusitis and bilateral NP were randomized into 3 study arms, 22 patients in each arm. After FESS, patients in the first and second groups were treated with clarithromycin 250 mg/day for 12 and 24 weeks, respectively, whereas patients in the third group did not receive any clarithromycin. Patients in all 3 groups received maintenance therapy with mometasone furoate 400 µg/day. Patient assessment was conducted before the surgery and 6, 12, and 24 weeks after surgery, using a visual analogue scale (VAS), 20-item SinoNasal Outcome Test (SNOT-20), acoustic rhinometry, rhinomanometry, saccharin transit time, nasal endoscopy, computed tomography (CT) of paranasal sinuses, and measurement of the level of eosinophil cationic protein (ECP) in their nasal secretions. RESULTS: The study confirmed efficacy of "long-term" macrolide therapy, resulting in significant improvement of all parameters except acoustic rhinometry and VAS in both clarithromycin groups as compared to the control. Concentration of ECP in the nasal secretions increased dramatically after surgery, then returned to baseline levels after 12 and 24 weeks of treatment with clarithromycin. In the control group, ECP level continued to increase and was significantly higher at the endpoint. Both groups with clarithromycin showed significantly better endoscopic and CT scores than the control group at the end point. CONCLUSION: "Long-term" low-dose clarithromycin 250 mg/day is able to control eosinophilic inflammation and prevent early relapse of NP after FESS.

Nasal deposition of ciclesonide nasal aerosol and mometasone aqueous nasal spray in allergic rhinitis patients.

BACKGROUND: Sensory attributes of intranasal corticosteroids, such as rundown to the back of the throat, may influence patient treatment preferences. This study compares the nasal deposition and nasal retention of a radiolabeled solution of ciclesonide nasal aerosol (CIC-hydrofluoroalkane [HFA]) with a radiolabeled suspension of mometasone furoate monohydrate aqueous nasal spray (MFNS) in subjects with either perennial allergic rhinitis (AR) or seasonal AR. METHODS: In this open-label, single-dose, randomized, crossover scintigraphy study, 14 subjects with symptomatic AR received a single dose of radiolabeled 74-µg CIC-HFA (37 µg/spray, 1 spray/each nostril) via a nasal metered-dose inhaler or a single dose of radiolabeled 200-µg MFNS (50 µg/spray, 2 sprays/each nostril), with a minimum 5-day washout period between treatments. Initial deposition (2 minutes postdose) of radiolabeled CIC-HFA and MFNS in the nasal cavity, nasopharynx, and on nasal wipes, and retention of radioactivity in the nasal cavity and nasal run-out on nasal wipes at 2, 4, 6, 8, and 10 minutes postdose were quantified with scintigraphy. RESULTS: At 2 and 10 minutes postdose, deposition of radiolabeled CIC-HFA was significantly higher in the nasal cavity versus radiolabeled MFNS (99.42% versus 86.50% at 2 minutes, p = 0.0046; and 81.10% versus 54.31% at 10 minutes, p < 0.0001, respectively; p values unadjusted for multiplicity). Deposition of radioactivity on nasal wipes was significantly higher with MFNS versus CIC-HFA at all five time points, and posterior losses of radiolabeled formulation were significantly higher with MFNS at 6, 8, and 10 minutes postdose. CONCLUSION: In this scintigraphic study, significantly higher nasal deposition and retention of radiolabeled aerosol CIC-HFA were observed versus radiolabeled aqueous MFNS in subjects with AR.

First randomized trial on clobetasol propionate and mometasone furoate in the treatment of vulvar lichen sclerosus: results of efficacy and tolerability.

BACKGROUND: A 3-month topical application of clobetasol propionate (CP) represents the recommended and accepted first-line treatment for vulvar lichen sclerosus (VLS); however, to date, no randomized controlled trials have compared the efficacy and safety of CP with other topical corticosteroids. OBJECTIVE: To compare the effectiveness and tolerability of two different topical corticosteroids, CP 0·05% ointment and mometasone furoate (MMF) 0·1% ointment, in the treatment of VLS. METHODS: Fifty-four patients with VLS were enrolled in a 12-week active treatment phase (ATP) and randomized to apply either CP or MMF in a tapering regimen. The main efficacy parameters were the response rate, the rate of patients achieving an improvement from baseline of ≥ 75% in the subjective and objective scores, and the mean reduction in subjective and objective scores throughout the treatment. RESULTS: By the end of the 12-week ATP, 24 (89%) patients were considered to be responders among the CP patients and 24 (89%) among the MMF patients; 59% and 37% of patients in the CP group and 67% and 48% in the MMF group achieved an improvement of at least 75% in subjective and objective scores, respectively. The decrease in mean symptom and sign scores was significant compared with baseline with both treatments. No significant differences were found in any of the assessed efficacy endpoints between CP and MMF. Both treatments were well tolerated. CONCLUSIONS: Clobetasol propionate and MMF appeared similarly efficacious and well tolerated for the treatment of VLS and both may represent the first-line treatment for the disease.