Efficacy and safety of CD24Fc in hospitalised patients with COVID-19: a randomised, double-blind, placebo-controlled, phase 3 study.

BACKGROUND: Non-antiviral therapeutic options are required for the treatment of hospitalised patients with COVID-19. CD24Fc is an immunomodulator with potential to reduce the exaggerated inflammatory response to tissue injuries. We aimed to evaluate the safety and efficacy of CD24Fc in hospitalised adults with COVID-19 receiving oxygen support. METHODS: We conducted a randomised, double-blind, placebo-controlled, phase 3 study at nine medical centres in the USA. Hospitalised patients (age ≥18 years) with confirmed SARS-CoV-2 infection who were receiving oxygen support and standard of care were randomly assigned (1:1) by site-stratified block randomisation to receive a single intravenous infusion of CD24Fc 480 mg or placebo. The study funder, investigators, and patients were masked to treatment group assignment. The primary endpoint was time to clinical improvement over 28 days, defined as time that elapsed between a baseline National Institute of Allergy and Infectious Diseases ordinal scale score of 2-4 and reaching a score of 5 or higher or hospital discharge. The prespecified primary interim analysis was done when 146 participants reached the time to clinical improvement endpoint. Efficacy was assessed in the intention-to-treat population. Safety was assessed in the as-treated population. This study is registered with ClinicalTrials.gov, NCT04317040. FINDINGS: Between April 24 and Sept 22, 2020, 243 hospitalised patients were assessed for eligibility and 234 were enrolled and randomly assigned to receive CD24Fc (n=116) or placebo (n=118). The prespecified interim analysis was done when 146 participants reached the time to clinical improvement endpoint among 197 randomised participants. In the interim analysis, the 28-day clinical improvement rate was 82% (81 of 99) for CD24Fc versus 66% (65 of 98) for placebo; median time to clinical improvement was 6·0 days (95% CI 5·0-8·0) in the CD24Fc group versus 10·0 days (7·0-15·0) in the placebo group (hazard ratio [HR] 1·61, 95% CI 1·16-2·23; log-rank p=0·0028, which crossed the prespecified efficacy boundary [α=0·0147]). 37 participants were randomly assigned after the interim analysis data cutoff date; among the 234 randomised participants, median time to clinical improvement was 6·0 days (95% CI 5·0-9·0) in the CD24Fc group versus 10·5 days (7·0-15·0) in the placebo group (HR 1·40, 95% CI 1·02-1·92; log-rank p=0·037). The proportion of participants with disease progression within 28 days was 19% (22 of 116) in the CD24Fc group versus 31% (36 of 118) in the placebo group (HR 0·56, 95% CI 0·33-0·95; unadjusted p=0·031). The incidences of adverse events and serious adverse events were similar in both groups. No treatment-related adverse events were observed. INTERPRETATION: CD24Fc is generally well tolerated and accelerates clinical improvement of hospitalised patients with COVID-19 who are receiving oxygen support. These data suggest that targeting inflammation in response to tissue injuries might provide a therapeutic option for patients hospitalised with COVID-19. FUNDING: Merck & Co, National Cancer Institute, OncoImmune.

Clinical and microbiological outcomes, by causative pathogen, in the ASPECT-NP randomized, controlled, Phase 3 trial comparing ceftolozane/tazobactam and meropenem for treatment of hospital-acquired/ventilator-associated bacterial pneumonia.

OBJECTIVES: In the ASPECT-NP trial, ceftolozane/tazobactam was non-inferior to meropenem for treating nosocomial pneumonia; efficacy outcomes by causative pathogen were to be evaluated. METHODS: Mechanically ventilated participants with hospital-acquired/ventilator-associated bacterial pneumonia were randomized to 3 g ceftolozane/tazobactam (2 g ceftolozane/1 g tazobactam) q8h or 1 g meropenem q8h. Lower respiratory tract (LRT) cultures were obtained ≤36 h before first dose; pathogen identification and susceptibility were confirmed at a central laboratory. Prospective secondary per-pathogen endpoints included 28 day all-cause mortality (ACM), and clinical and microbiological response at test of cure (7-14 days after the end of therapy) in the microbiological ITT (mITT) population. RESULTS: The mITT population comprised 511 participants (264 ceftolozane/tazobactam, 247 meropenem). Baseline LRT pathogens included Klebsiella pneumoniae (34.6%), Pseudomonas aeruginosa (25.0%) and Escherichia coli (18.2%). Among baseline Enterobacterales isolates, 171/456 (37.5%) were ESBL positive. For Gram-negative baseline LRT pathogens, susceptibility rates were 87.0% for ceftolozane/tazobactam and 93.3% for meropenem. For Gram-negative pathogens, 28 day ACM [52/259 (20.1%) and 62/240 (25.8%)], clinical cure rates [157/259 (60.6%) and 137/240 (57.1%)] and microbiological eradication rates [189/259 (73.0%) and 163/240 (67.9%)] were comparable with ceftolozane/tazobactam and meropenem, respectively. Per-pathogen microbiological eradication for Enterobacterales [145/195 (74.4%) and 129/185 (69.7%); 95% CI: -4.37 to 13.58], ESBL-producing Enterobacterales [56/84 (66.7%) and 52/73 (71.2%); 95% CI: -18.56 to 9.93] and P. aeruginosa [47/63 (74.6%) and 41/65 (63.1%); 95% CI: -4.51 to 19.38], respectively, were also comparable. CONCLUSIONS: In mechanically ventilated participants with nosocomial pneumonia owing to Gram-negative pathogens, ceftolozane/tazobactam was comparable with meropenem for per-pathogen 28 day ACM and clinical and microbiological response.

A phase 3 study evaluating the safety and efficacy of a pediatric dose of mometasone furoate with and without formoterol for persistent asthma.

OBJECTIVES: Asthma affects over 6 million children in the United States alone. This study investigated the efficacy and long-term safety of mometasone furoate-formoterol (MF/F) and MF monotherapy in children with asthma. MATERIALS AND METHODS: This phase 3, multicenter, randomized controlled trial evaluated metered-dose inhaler twice daily (BID) dosing with MF/F 100/10 µg or MF 100 µg in children, aged 5 to 11 years, with a history of asthma for greater than or equal to 6 months and confirmed bronchodilator reversibility, who were adequately controlled on inhaled corticosteroid/long-acting beta-agonist combination therapy for greater than or equal to 4 weeks. After a 2-week run-in on MF 100 µg BID, eligible patients received 24 weeks of double-blind treatment and were followed for safety up to 26 weeks. The primary efficacy endpoint was the change from baseline in AM postdose 60-minute AUC %predicted FEV1% across 12 weeks of treatment. RESULTS: A total of 181 participants received at least one dose of MF/F (n = 91) or MF (n = 90). MF/F was superior to MF across the 12-week evaluation period, with a treatment advantage of 5.21 percentage points (P < .001). Superior onset of action with MF/F over MF was achieved as early as 5 minutes postdose on day 1. Overall, approximately 50% of participants experienced one or more treatment-emergent adverse events, with fewer occurring in the MF/F group. CONCLUSIONS: In children 5 to 11 years of age with persistent asthma, the addition of F to MF was well tolerated and provided significant, rapid, and sustained improvement in lung function compared with MF alone.

Serious Asthma Outcomes and Asthma Exacerbations with Maintenance on Inhaled Corticosteroid (Mometasone Furoate)/Long-Acting Beta Agonist (Formoterol) Combination Compared to Step Down to Mometasone Monotherapy.

BACKGROUND: Because of historical safety concerns with the use of long-acting ß-agonists (LABA) in asthma, step-down from inhaled corticosteroid (ICS)/LABA combination therapy to ICS monotherapy is recommended once asthma control is achieved. OBJECTIVE: To evaluate the benefit/risk question about whether patients with asthma who achieve disease control on fixed-dose ICS/LABA combination therapy, such as mometasone furoate/formoterol fumarate (MF/F), should continue with this therapy or be stepped down to ICS monotherapy, such as MF. METHODS: Using data from 8447 clinically stable patients with persistent asthma in the Safety Pharma Investigation of Respiratory Outcomes trial who had been receiving a stable dose of ICS/LABA for ≥4 weeks, this post hoc analysis evaluated the risk of serious asthma outcomes (SAOs) (adjudicated hospitalization, intubation, or death) and asthma exacerbation (AEX) (composite of hospitalizations ≥24 hours, emergency visits <24 hours requiring systemic corticosteroid, or systemic corticosteroid for ≥3 consecutive days) in participants randomized to remain on ICS/LABA (MF/F) or step down to ICS (MF) for 26 weeks. RESULTS: There was no significant difference in SAO risk among patients maintained on ICS/LABA with MF/F compared with those who stepped down from ICS/LABA to MF (hazard ratio [HR], 1.03 [95% confidence interval (CI): 0.61, 1.75], P = .913). The risk of AEX was significantly lower in patients maintained on ICS/LABA with MF/F compared with those who stepped down from ICS/LABA to MF (HR, 0.87 [95% CI: 0.78, 0.98], P = .020). CONCLUSIONS: In this post hoc analysis of a large clinical trial dataset, maintenance on ICS/LABA with MF/F is not associated with an increased risk of SAOs and also significantly reduces the risk of AEX compared with step-down from ICS/LABA to MF.

Effect of mometasone furoate nasal spray on moderate-to-severe nasal congestion in seasonal allergic rhinitis: A responder analysis.

Background: Nasal congestion is consistently identified as the most bothersome symptom of seasonal allergic rhinitis (SAR), and, in guidelines, intranasal corticosteroids are the preferred treatment for nasal congestion. Objective: The aim of this post hoc cumulative responder analysis was to examine the nasal congestion response in detail by depicting the level of response obtained in two double-blind, placebo controlled studies of mometasone furoate nasal spray (MFNS) therapy for SAR, conducted from August to October 2008 at U.S. sites, in which nasal congestion was prespecified as the primary end point. Methods: Patients ≥12 years of age with a ≥2-year SAR history, positive skin test result, and moderate or severe nasal congestion were randomly assigned to once-daily treatment in the morning with MFNS or placebo for 15 days. The primary end point was the change from baseline in morning and evening reflective nasal congestion scores averaged over days 1-15. Treatment response, which ranged from >0% to >90% improvement, was evaluated at 10% intervals; >30% and >50% improvements were further evaluated by using the Mietinnen-Nurminen method weighted by study to test the differences of proportions. The Breslow-Day equal odds ratios test was used to justify pooling. Results: Of the 344 and 340 patients in the MFNS and placebo groups, respectively, the proportions of patients who experienced a >30% response in nasal congestion, averaged over 15 days, were 37% versus 19% in the MFNS and placebo groups, respectively (p < 0.001). Those who experienced a >50% response were 13% and 7%, respectively (p = 0.003). Among the patients treated with MFNS, the mean response was greater during the second versus the first week of treatment. There was no difference between responses in the morning versus evening or for patients with moderate versus severe nasal congestion at baseline. Conclusion: MFNS is effective in relieving moderate-to-severe nasal congestion in patients with SAR. The response to MFNS is maintained with once-daily administration and improves with continuous use over 2 weeks.

A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia.

BACKGROUND: Posaconazole (POS) is a potent triazole antifungal agent approved in adults for treatment and prophylaxis of invasive fungal infections (IFIs). The objectives of this study were to evaluate the pharmacokinetics (PK), safety, and tolerability of POS oral suspension in pediatric subjects with neutropenia. METHODS: This was a prospective, multicenter, sequential dose-escalation study. Enrolled subjects were divided into 3 age groups: AG1, 7 to <18 years; AG2, 2 to <7 years; and AG3, 3 months to <2 years. AG1 and AG2 were divided into 3 dosage cohorts: DC1, 12 mg/kg/day divided twice daily (BID); DC2, 18 mg/kg/day BID; and DC3, 18 mg/kg/day divided thrice daily (TID). AG3 was also divided into DC1 and DC2; however, no subjects were enrolled in DC2. Subjects received 7-28 days of POS oral suspension. PK samples were collected at predefined time points. The POS PK target was predefined as ~90% of subjects with Cavg (AUC /dosing interval) between 500 and 2500 ng/mL, with an anticipated mean steady state Cavg exposure of ~1200 ng/mL. RESULTS: The percentage of subjects meeting the PK target was <90% across all age groups and dosage cohorts (range: 31% to 80%). The percentage of subjects that achieved the Cavg target of 500 to 2500 ng/mL on Day 7 ranged from 31% to 80%, with the lowest proportion in subjects 2 to <7 years receiving 12 mg/kg/day BID (AG2/DC1) and the highest proportion in subjects 7 to <18 years receiving 18 mg/kg/day TID (AG1/DC3). At all three dose levels (12 mg/kg/day BID, 18 mg/kg/day BID and 18 mg/kg/day TID), subjects in AG1 (7 to <18 years old) had higher mean PK exposures at steady state than those in AG2. High variability in exposures was observed in all groups. POS oral suspension was generally well tolerated and most of the reported adverse events were related to the subjects' underlying diseases. CONCLUSION: The POS PK target of 90% of subjects with Cavg between 500 and 2500 ng/mL was not achieved in any of the age groups across the different dosage cohorts. New formulations of the molecule with a greater potential to achieve the established PK target are currently under investigation. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01716234.

Serious asthma events with mometasone furoate plus formoterol compared with mometasone furoate.

BACKGROUND: The safety of long-acting ß-agonists added to inhaled corticosteroids for the treatment of persistent asthma has been controversial. OBJECTIVE: We sought to determine whether administering formoterol in combination with mometasone furoate increases the risk of serious asthma outcomes (SAOs) compared with mometasone furoate alone. This clinical trial is registered as NCT01471340. METHODS: We conducted a 26-week, randomized, double-blind trial in adolescent and adult patients (≥12 years) with persistent asthma in 35 countries with the primary objective of evaluating whether mometasone furoate-formoterol increases the risk of SAOs (adjudicated hospitalization, intubation, or death) compared with mometasone furoate alone. The key efficacy end point was asthma exacerbation (composite of hospitalization of ≥24 hours, emergency department visits of <24 hours requiring systemic corticosteroids, or use of systemic corticosteroids for ≥3 consecutive days). RESULTS: Among 11,729 patients (mometasone furoate-formoterol, n = 5,868; mometasone furoate, n = 5,861), a total of 81 SAOs, all asthma-related hospitalizations, were observed in 71 patients: 45 events from 39 patients receiving mometasone furoate-formoterol and 36 events from 32 patients receiving mometasone furoate. The hazard ratio for the first SAO in the mometasone furoate-formoterol versus mometasone furoate group was 1.22 (95% CI, 0.76-1.94; P = .411). Asthma exacerbation occurred in 1,487 patients: 708 receiving mometasone furoate-formoterol and 779 receiving mometasone furoate. The hazard ratio for the first asthma exacerbation in the mometasone furoate-formoterol versus mometasone furoate group was 0.89 (95% CI, 0.80-0.98; P = .021). CONCLUSIONS: The addition of formoterol to mometasone furoate maintenance therapy did not increase the risk of serious asthma-related events and reduced the risk of asthma exacerbation.

Corifollitropin alfa versus recombinant follicle-stimulating hormone: an individual patient data meta-analysis.

A meta-analysis was conducted of individual patient data (n = 3292) from three randomized controlled trials of corifollitropin alfa versus rFSH: Engage (150 µg corifollitropin alfa n = 756; 200 IU rFSH n = 750), Ensure (100 µg corifollitropin alfa n = 268; 150 IU rFSH n = 128), and Pursue (150 µg corifollitropin alfa n = 694; 300 IU rFSH n = 696). Women with regular menstrual cycles aged 18-36 and body weight >60 kg (Engage) or ≤60 kg (Ensure), or women aged 35-42 years and body weight ≥50 kg (Pursue), received a single injection (100 µg or 150 µg) of corifollitropin alfa (based on body weight and age) or daily rFSH. The difference (corifollitropin alfa minus rFSH) in the number of oocytes retrieved was +1.0 (95% CI: 0.5-1.5); vital pregnancy rate: -2.2% (95% CI: -5.3%-0.9%); ongoing pregnancy rate: -1.7% (95% CI: -4.7%-1.4%); and live birth rate: -2.0% (95% CI: -5.0%-1.1%). The odds ratio for overall OHSS was 1.15 (95% CI: 0.82-1.61), and for moderate-to-severe OHSS: 1.29 (95% CI: 0.81-2.05). A single dose of corifollitropin alfa for the first 7 days of ovarian stimulation is a generally well-tolerated and similarly effective treatment compared with daily rFSH.

Efficacy and safety of frozen-thawed embryo transfer in women aged 35 to 42 years from the PURSUE randomized clinical trial.

OBJECTIVE: To examine the efficacy and safety of frozen-thawed embryo transfer (FTET) cycles with supernumerary embryos cryopreserved during a randomized clinical trial (PURSUE). DESIGN: Follow-up clinical study. SETTING: In vitro fertilization (IVF) centers. PATIENT(S): Infertile women 35 to 42 years of age. INTERVENTION(S): In PURSUE, women were randomized to a single injection of 150 µg of corifollitropin alfa (n = 694) or daily 300 IU of recombinant follicle-stimulating hormone (recombinant FSH; n = 696) for the first 7 days of controlled ovarian stimulation (COS) in a gonadotropin-releasing hormone (GnRH) antagonist protocol. MAIN OUTCOME MEASURE(S): Cumulative vital pregnancy rate per-patient by treatment group, cumulative live-birth rate per-patient by treatment group, and occurrence of adverse events in (pregnant) women and their fetuses/infants and the incidence of congenital malformations in the infants. RESULT(S): Of the 1,390 treated women in PURSUE, 307 were enrolled in the FTET study. In PURSUE or a subsequent FTET cycle, the cumulative vital pregnancy rate (per patient) was 31.1% (95% confidence interval [CI], 27.7%; 34.7%) with corifollitropin alfa versus 33.0% (95% CI: 29.6%; 36.7%) with recombinant FSH; treatment difference, -1.8% (95% CI, -6.5%; 3.0%), and the cumulative live-birth rate (per patient) was 28.2% (95% CI, 24.9%; 31.8%) with corifollitropin alfa versus 29.5% (95% CI, 26.1%; 33.0%) with recombinant FSH; treatment difference, -1.2% (95% CI, -5.7%; 3.4%). There were no clinically relevant differences in safety outcomes collected from pregnant women or their infants after transfer of cryopreserved embryos obtained by treatment with corifollitropin alfa or recombinant FSH. CONCLUSION(S): The cumulative vital pregnancy and live-birth rates (from fresh cycles and FTET) were similar in women treated with corifollitropin alfa and recombinant FSH. No new safety signals were detected in this follow-up FTET study. CLINICAL TRIAL REGISTRATION NUMBER: NCT01146418.

Prediction of Ovarian Hyperstimulation Syndrome in Patients Treated with Corifollitropin alfa or rFSH in a GnRH Antagonist Protocol.

STUDY QUESTION: What is the threshold for the prediction of moderate to severe or severe ovarian hyperstimulation syndrome (OHSS) based on the number of growing follicles ≥ 11 mm and/or estradiol (E2) levels? SUMMARY ANSWER: The optimal threshold of follicles ≥11 mm on the day of hCG to identify those at risk was 19 for both moderate to severe OHSS and for severe OHSS. Estradiol (E2) levels were less prognostic of OHSS than the number of follicles ≥ 11 mm. WHAT IS KNOWN ALREADY: In comparison to long gonadotropin-releasing hormone (GnRH) agonist protocols, the risk of severe OHSS is reduced by approximately 50% in a GnRH antagonist protocol for ovarian stimulation prior to in vitro fertilisation (IVF), while the two protocols provide equal chances of pregnancy per initiated cycle. Nevertheless, moderate to severe OHSS may still occur in GnRH antagonist protocols if human chorionic gonadotropin (hCG) is administered to trigger final oocyte maturation, especially in high responder patients. Severe OHSS following hCG trigger may occur with an incidence of 1-2% in a relatively young (aged 18 to 36 years) IVF population treated in a GnRH-antagonist protocol. STUDY DESIGN, SIZE, DURATION: From the Engage, Ensure and Trust trials, in total, 2,433 women who received hCG for oocyte maturation and for whom the number of follicles ≥ 11 mm and the level of E2 on the day of hCG administration were known were included in the analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: The threshold for OHSS prediction of moderate and severe OHSS was assessed in women treated with corifollitropin alfa or daily recombinant follicle stimulation hormone (rFSH) in a gonadotropin-releasing hormone (GnRH)-antagonist protocol. Receiver operating characteristics curve analyses for moderate to severe OHSS and severe OHSS were performed on the combined dataset and the sensitivity and specificity for the optimal threshold of number of follicles ≥ 11 mm, E2 levels on the day of (hCG), and a combination of both, were determined. MAIN RESULTS AND THE ROLE OF CHANCE: The optimal threshold of follicles ≥ 11 mm on the day of hCG to identify those at risk of moderate to severe OHSS was 19 (sensitivity and specificity 62.3% and 75.6%, respectively) and for severe OHSS was also 19 (sensitivity and specificity 74.3% and 75.3%, respectively). The positive and negative predictive values were 6.9% and 98.6%, respectively, for moderate to severe OHSS, and 4.2% and 99.5% for severe OHSS. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective analysis of combined data from three trials following ovarian stimulation with two different gonadotropins. WIDER IMPLICATIONS OF THE FINDINGS: For patients with 19 follicles or more ≥11 mm on the day of hCG, measures to prevent the development of OHSS should be considered. Secondary preventive measures include cycle cancellation or coasting, use of a GnRH agonist to trigger final oocyte maturation in place of hCG and a freeze all strategy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00702845 NCT00696800 NCT00696878.

Osteoarthritis patients with pain improvement are highly likely to also have improved quality of life and functioning. A post hoc analysis of a clinical trial.

BACKGROUND: This analysis evaluated whether osteoarthritis patients achieving the greatest pain control and lowest pain states also have the greatest improvement in functioning and quality of life. METHODS: Patients (n=419) who failed prior therapies and who were switched to etoricoxib 60mg were categorized as pain responders or non-responders at 4 weeks based on responder definitions established by the Initiative on Methods, Measurement, and Pain (IMMPACT) criteria, including changes from baseline of ≥15%, ≥30%, ≥50%, ≥70% and a final pain status of ≤3/10 (no worse than mild pain). Pain was assessed at baseline and 4 weeks using 4 questions from the Brief Pain Inventory (BPI) (worst pain, least pain, average pain, and pain right now), and also using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain subscale. We examined the relationship between pain responses with changes from baseline in two functional measures (the BPI Pain Interference questions and the WOMAC Function Subscale) as well as changes from baseline in quality of life (assessed on the SF-36 Physical and Mental Component Summaries). We also sought to understand whether these relationships were influenced by the choice of the pain instrument used to assess response. We contrast the mean difference in improvements in the functional and quality of life instruments based on pain responder status (responder versus non-responder) and the associated 95% confidence limits around this difference. RESULTS: Patients with better pain responses were much more likely to have improved functional responses and improved quality of life, with higher mean changes in these outcomes versus pain non-responders, regardless of the choice of IMMPACT pain response definition (e.g., using any of 15%, 30%, 50%, 70% change from baseline) or the final pain state of ≤3/10. There was an evident gradient, where higher levels of pain response were associated with greater mean improvements in function and quality of life. The finding that greater pain responses led to greater functional improvements and quality of life gains was not dependent on the manner in which pain was evaluated. Five different pain instruments (e.g., the 4 questions on pain from the BPI pain questionnaire and the WOMAC pain subscale) consistently demonstrated that pain responders had statistically significantly greater improvements in function and quality of life compared to pain non-responders. This suggests these results are likely to be generalizable to any validated pain measure for osteoarthritis. CONCLUSIONS: Pain is an efficient outcome measure for predicting broader patient response in osteoarthritis. Patients who do not achieve timely, acceptable pain states over 4 weeks were less likely to experience functional or quality of life improvements. IMPLICATIONS: Good pain improvements in osteoarthritis with a valid pain instrument are a proxy for good improvements in both function and quality of life. Therefore proper osteoarthritis pain assessment can lead to efficient evaluations in the clinic.

Intercycle variability of the ovarian response in patients undergoing repeated stimulation with corifollitropin alfa in a gonadotropin-releasing hormone antagonist protocol.

OBJECTIVE: To determine whether individual subject variation in ovarian response between repeated cycles with the same ovarian stimulation protocol can be predicted. DESIGN: Retrospective data analysis. SETTING: Multicenter, open-label, uncontrolled clinical trial. PATIENT(S): Women aged 18-39 from a phase 3, open-label, uncontrolled trial with complete data across all cycles (n = 176). INTERVENTION(S): Up to three cycles of a single injection of 150 µg corifollitropin alfa for 7 days, then daily recombinant FSH/hMG until three follicles reached ≥17 mm. Gonadotropin-releasing hormone antagonist from stimulation day 5 until day of hCG administration. MAIN OUTCOME MEASURE(S): Numbers of follicles ≥11 mm on day of hCG in cycles 1-3, transition in ovarian response type between cycles from low (0-<6), normal (6-<18), and high (≥18), and serum FSH concentrations and antral follicle count (AFC) at each cycle start. RESULT(S): The mean (SD) numbers of follicles ≥11 mm on day of hCG were 13.4 (6.2), 13.3 (5.4), and 13.8 (6.4) in cycles 1, 2 and 3, respectively. Between cycles 1 and 2, 11.9% switched from normal to low or high response, and 12.5% switched from low or high to normal response; 75.6% remained in the same category. Between cycles 2 and 3, 15.9% switched from normal to low or high response, and 10.2% switched from low or high to normal response; 73.9% remained in the same category. These shifts are symmetrical in nature, in that the percentage of subjects who shift from normal to low or high response is comparable to the percentage of subjects who shift from low or high to normal response. Baseline FSH and AFC did not significantly predict transition in ovarian response. CONCLUSION(S): The variability in ovarian responses between repeated cycles using the same protocol was not explained by baseline FSH and AFC. CLINICAL TRIAL REGISTRATION NUMBER: NCT00696878 Protocol P05714.

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.).

Relieving nasal congestion in children with seasonal and perennial allergic rhinitis: efficacy and safety studies of mometasone furoate nasal spray.

BACKGROUND: In surveys of children with allergic rhinitis (AR), nasal congestion has been identified as the most frequently experienced and bothersome symptom. This analysis was conducted to investigate the effect of mometasone furoate nasal spray (MFNS) on congestion in children with AR. METHODS: Two multicenter, double-blind, placebo-controlled studies randomly assigned children to MFNS 100 µg or placebo, 1 spray/nostril QD for 4 weeks (Study 1: ages 6-11 years with seasonal AR [SAR] ≥1 year; Study 2: ages 3-11 years with perennial AR [PAR] ≥1 year). Least square (LS) means were obtained from an ANCOVA model with treatment and study center effects, with baseline score as a covariate. We conducted post hoc evaluation of changes from baseline in AM/PM PRIOR (average of reflective AM and PM scores) nasal congestion (0=none to 3=severe). RESULTS: Study 1: MFNS (n=134) reduced congestion significantly more than placebo (n=135) on day 2 (P=.004) and on 23/29 days (P≤.037). Change from baseline was -0.53 and -0.28 for MFNS and placebo (P<.001) over days 1-15 and -0.64 and -0.38 for MFNS and placebo (P<.001) over days 1-29. Study 2: MFNS (n=185) reduced congestion significantly more than placebo (n=189) on day 3 (P=.015) and on 22/29 days (P≤.047). Change from baseline was -0.56 and -0.36 for MFNS and placebo (P<.001) over days 1-15 and -0.64 and -0.45 for MFNS and placebo (P<.001) over days 1-29. MFNS was well tolerated, with no unusual or unexpected adverse events. CONCLUSION: MFNS effectively relieved nasal congestion and was well tolerated in children with SAR or PAR.

Dose-dependent anti-inflammatory effect of inhaled mometasone furoate/formoterol in subjects with asthma.

OBJECTIVE: A well-controlled study in patients with allergic asthma was warranted to assess dose-dependency between fractional concentration of exhaled nitric oxide (FeNO) and sputum eosinophils to a combination of an inhaled corticosteroid plus a long-acting ß2-agonist. We sought to characterize the dose-dependency of mometasone furoate/formoterol (MF/F) using FeNO and sputum eosinophil percentage as surrogates of airway inflammation in subjects with allergic asthma. METHODS: Following a 2-week, open-label run-in, 93 subjects (≥12 y) using only short-acting beta agonist reliever medication as needed, were randomized to twice daily (BID) placebo; MF/F 100/10 µg, 200/10 µg, or 400/10 µg (via pressurized metered-dose inhaler [MDI]); MF-MDI 200 µg; or MF 200 µg via dry powder inhaler (DPI) during a 2-week, double-blind treatment period. RESULTS: All active treatments demonstrated significant percentage reductions from baseline in FeNO compared with placebo at all time points (P ≤ 0.034). At endpoint, mean MF/F treatment group FeNO reductions ranged from -35.3% to -61.4%. Sputum eosinophil percentage reductions from baseline were significant compared with placebo for the MF/F 200/10 µg, MF/F 400/10 µg, and MF-DPI 200 µg groups at endpoint (P ≤ 0.023). Escalating MF/F doses significantly reduced both FeNO (P ≤ 0.001) and sputum eosinophil (P ≤ 0.022) levels in a dose-dependent manner at all time points. All treatments were well tolerated; no serious adverse events were observed. CONCLUSION: All 3 MF/F doses demonstrated pronounced, clinically meaningful, dose-dependent reductions in FeNO, with reduced sputum eosinophil levels for MF/F 200/10 µg and MF/F 400/10 µg. These findings suggest both inflammatory markers may be useful in assessing corticosteroid responsiveness in asthma patients, and perhaps identifying the same asthma subphenotype. Clinical Trials.gov: NCT00635882.

The asthma disease activity score: a discriminating, responsive measure predicts future asthma attacks.

BACKGROUND: Classifying asthma severity or activity has evolved, but there are no published weighted composite measures of asthma disease activity that account for the relative importance of the many individual clinical variables that are widely used. OBJECTIVES: We sought to develop a weighted and responsive measure of asthma disease activity. METHODS: Discriminant and multiple regression analyses based on 2 previously conducted clinical trials were used to develop the Asthma Disease Activity Score (ADAS-6). RESULTS: The ADAS-6 demonstrated content validity because its components assess different manifestations of asthma: FEV(1) (percent predicted), Asthma Quality of Life Questionnaire-Symptom domain, rescue ß-agonist use, nocturnal awakenings, peak expiratory flow diurnal variability, and rescue ß-agonist use diurnal variability. The ADAS-6 demonstrated cross-sectional and longitudinal validity. It was discriminating: it distinguished levels of disease activity and response to different treatment intensities (P < .0001). Similar results were obtained with an independent clinical trial. The ADAS-6 was highly responsive to treatment effects, with a standardized effect size exceeding that of other widely used outcome measures. Using ADAS-6 as the primary end point in the montelukast pivotal trials would have significantly reduced the sample size needed to detect a comparable change in outcome. Furthermore, increments in the ADAS-6 predicted the risk of future asthma attacks. A simplified Asthma Disease Activity Score 4-variable version (ADAS-4) demonstrated similar measurement properties. CONCLUSIONS: The ADAS-6 and ADAS-4 are novel, weighted, and responsive measures of asthma disease activity. Use of these measures in clinical trials might better separate treatment effects, predict future asthma attacks, and substantially reduce sample size.

Effects of intranasal mometasone furoate on itchy ear and palate in patients with seasonal allergic rhinitis.

BACKGROUND: Intranasal steroids relieve nasal symptoms and ocular itch in allergic rhinitis. Itchy ear and palate are also common and bothersome symptoms but have received little attention in clinical trials of allergic rhinitis. OBJECTIVE: To ascertain the efficacy of mometasone furoate nasal spray in alleviating itchy ear and palate in seasonal allergic rhinitis. METHODS: Data were pooled from 4 randomized, double-blind, placebo-controlled trials of mometasone furoate nasal spray, 200 µg/d. Participants rated ear and palate itching from baseline through treatment day 15 as follows: 0, none; 1, mild; 2, moderate; and 3, severe. RESULTS: A total of 962 study participants received mometasone furoate nasal spray or placebo. Baseline least squares mean itchy ear and palate score was 1.81 for participants receiving mometasone furoate nasal spray (n = 480) and 1.85 for participants receiving placebo (n = 482). Mometasone furoate nasal spray was associated with a greater decrease in itchy and ear palate score vs placebo during the 15-day study period (least squares mean change, -0.73 vs -0.45; P < .001). The difference reached significance on day 2 and persisted through day 15 (P ≤ .01 for each day). Results were similar in a subgroup of patients (n = 305) with moderate-to-severe symptoms at baseline. Adverse events with mometasone furoate nasal spray were similar to those observed in other studies of intranasal steroid therapy. CONCLUSION: These preliminary findings suggest that mometasone furoate nasal spray effectively treats itchy ear and palate in individuals with seasonal allergic rhinitis. Itchy ear and palate is a relevant end point for future clinical trials of allergic rhinitis.

Mometasone furoate nasal spray increases the number of minimal-symptom days in patients with acute rhinosinusitis.

BACKGROUND: Acute rhinosinusitis (ARS) is triggered by viral or, uncommonly, bacterial infection, causing inflammatory symptoms for ≤12 weeks. OBJECTIVE: To investigate effects of mometasone furoate nasal spray (MFNS) vs amoxicillin and placebo on minimal-symptom days. METHODS: A double-blind, parallel-group, placebo- and active-controlled 15-day study randomly assigned patients 12 years of age or older to MFNS 200 µg twice daily, MFNS 200 µg once daily, amoxicillin 500 mg 3 times daily, or placebo. Patients had baseline rhinosinusitis major symptom score (MSS; combined rhinorrhea, postnasal drip, congestion, sinus headache, facial pain) of ≥5 and ≤12 (maximum: 15) for 7 to 28 days; scores were similar among groups. Minimal-symptom days and minimal-congestion days were defined post hoc by average am/pm MSS ≤4 and average AM/PM congestion ≤1. RESULTS: MFNS twice daily (n = 234) showed more minimal-symptom days vs placebo (n = 246) (62.69% vs 50.33%; P < .0001) or amoxicillin (n = 248) (54.35%; P = .0040). The MFNS QD was associated with numerically more minimal-symptom days than amoxicillin or placebo (54.72%; P ≤ .8982). MFNS was associated with more minimal-congestion days than placebo (72.97%, 67.73%, and 56.67% for twice daily, once daily, and placebo; P < .0001, each vs placebo) and MFNS BID with more minimal-congestion days than amoxicillin (72.97% vs 64.15%; P = .0007). Median time to first minimal-symptom day sustained until study end was 8.5 days for MFNS BID vs. 11 for placebo (P = .0085). CONCLUSION: MFNS 200 µg twice daily significantly increased minimal-symptom days vs amoxicillin or placebo in patients with ARS. Results of this intranasal corticosteroids (INS) therapy indicate it can improve outcomes and potentially reduce inappropriate antibiotic use.

Efficacy and safety characteristics of mometasone furoate/formoterol fumarate fixed-dose combination in subjects with moderate to very severe COPD: findings from pooled analysis of two randomized, 52-week placebo-controlled trials.

BACKGROUND: The clinical efficacy and safety of a mometasone furoate/formoterol fumarate (MF/F) fixed-dose combination formulation administered via a metered-dose inhaler was investigated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD). METHODS: Two 52-week, multicenter, double-blind, placebo-controlled trials with identical study designs were conducted in current or ex-smokers (aged ≥40 years), and pooled study results are presented herein. Subjects (n = 2251) were randomized to 26 weeks of twice-daily treatment with MF/F 400/10 µg, MF/F 200/10 µg, MF 400 µg, F 10 µg, or placebo. After the 26-week treatment period, placebo subjects completed the trial and 75% of subjects on active treatment entered a 26-week safety extension. Coprimary efficacy variables were mean changes in forced expiratory volume in one second (FEV(1)), area under the curve from 0 to 12 hours postdose (AUC(0-12 h)), and morning predose/trough FEV(1) from baseline to the week 13 endpoint. Key secondary efficacy variables were St George's Respiratory Questionnaire scores, symptom-free nights, time-to-first exacerbation, and partly stable COPD at the week 26 endpoint. RESULTS: In the 26-week treatment period, significantly greater increases in FEV(1) AUC(0-12 h) occurred with MF/F 400/10 versus MF 400 and placebo at the week 13 and week 26 endpoints (P ≤ 0.032). These increases were over three-fold greater with MF/F 400/10 than with MF 400. Also, significantly greater increases in morning predose/trough FEV(1) occurred with MF/F 400/10 versus F 10 and placebo at the week 13 endpoint (P < 0.05). The increase was four-fold greater with MF/F 400/10 than with F 10. All active treatment groups achieved minimum clinically important differences from baseline (>4 units) in St George's Respiratory Questionnaire scores at week 26. Symptom-free nights increased by ≥14% in the MF/F 400/10, MF 400, and F 10 groups (P ≤ 0.033 versus placebo). The incidence of exacerbations was lower in the MF/F groups (≤33.3%) than it was in the MF, formoterol, and placebo groups (≥33.8%) over the 26-week treatment period. The incidence of adverse events was similar in the active-treated and placebo-treated subjects across 26 weeks of treatment. Over the 1-year study period, there were no notable differences in the incidence or types of adverse events between the MF/F 400/10 and MF/F 200/10 groups compared with the MF or formoterol groups. Differences in rates of individual treatment-emergent adverse events were <3% between treatment groups. Rates of pneumonia were low (≤2%) across all treatment groups. CONCLUSION: Patients treated with MF/F demonstrated significant improvements in lung function, health status, and exacerbation rates. Although significant improvements were seen with both doses, a trend showing a dose-response effect was observed in the lung function measurements.

Symptom suppression in subjects with perennial allergic rhinitis treated with mometasone furoate nasal spray.

BACKGROUND: Allergic rhinitis (AR) carries a high symptom burden and impact on quality of life. The ability of an AR treatment to achieve and sustain symptom suppression would be expected to enhance quality of life and improve long-term outcomes. METHODS: In this ad hoc analysis of data from 4 phase 3 clinical trials of mometasone furoate nasal spray (MFNS), subjects with perennial AR recorded the severity of nasal symptoms twice daily for 12 weeks on a 4-point scale to determine the total nasal symptom score. RESULTS: In the pooled sample of 1,149 subjects, 580 received MFNS 200 µg per day and 569 received placebo. Significantly more subjects receiving MFNS achieved symptom suppression versus those receiving placebo: 63.3% (n = 367) versus 51.0% (n = 290; p < 0.001). Median time to suppression was significantly shorter with MFNS versus placebo (29 vs. 59 days; p < 0.001). Total suppression was achieved in a significantly greater percentage of patients receiving MFNS versus placebo (36.0 vs. 25.5%; p < 0.001). CONCLUSIONS: A high level of symptom relief is attained faster and sustained longer with MFNS. This analysis validates the importance of treatment adherence to achieve optimal, sustained symptom relief.