Publications by authors named "Lawrence Sher"

20 Publications

  • Page 1 of 1

Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma.

Am J Clin Dermatol 2021 Jan;22(1):101-115

Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA.

Background: Conjunctivitis is a known comorbidity of atopic dermatitis. Dupilumab clinical trials for moderate-to-severe atopic dermatitis in adults showed a higher conjunctivitis incidence for dupilumab-treated patients than placebo-treated patients, whereas trials for uncontrolled asthma reported lower rates for both dupilumab and placebo.

Objective: The objective of this study was to evaluate the incidence and severity of conjunctivitis in dupilumab clinical trials in adolescents with moderate-to-severe atopic dermatitis or uncontrolled asthma.

Methods: We evaluated the incidence of conjunctivitis in adolescents (aged 12 to < 18 years) in three phase III trials. Ocular events were diagnosed and treated based on patient-reported symptoms and an external eye examination by study investigators, in most cases without an ophthalmologic referral. In LIBERTY AD ADOL (16-week, randomized, placebo-controlled, double-blinded trial), adolescents with moderate-to-severe atopic dermatitis were randomized to subcutaneous placebo, dupilumab 300 mg every 4 weeks, or dupilumab every 2 weeks (200 mg, patients < 60 kg at baseline; 300 mg, ≥ 60 kg at baseline). In LIBERTY AD PED-OLE (open-label extension), pediatric patients from previous dupilumab atopic dermatitis trials received dupilumab 2 mg/kg or 4 mg/kg weekly (up to 300 mg) or 300 mg every 4 weeks. In LIBERTY ASTHMA QUEST (randomized, double-blinded, placebo-controlled trial), patients with uncontrolled moderate-to-severe asthma were randomized to 52 weeks of add-on therapy with dupilumab 200 or 300 mg every 2 weeks or matched-volume placebo.

Results: In ADOL, more dupilumab-treated (17/165; 10.3%) than placebo-treated patients (4/85; 4.7%) reported one or more conjunctivitis event. All events were mild to moderate in severity; 12 (7.3%) dupilumab-treated and 4 (4.7%) placebo-treated patients received treatment. Most patients with conjunctivitis (dupilumab, 12/17; placebo, 4/4) recovered/resolved during the treatment period. The risk of conjunctivitis showed no relationship with dupilumab serum concentration. In PED-OLE, 12/275 adolescents (4.4%) reported one or more conjunctivitis event. Most conjunctivitis events were mild to moderate. Ten patients received treatment for conjunctivitis. Ten patients recovered/resolved during the study. In QUEST, similar low proportions of dupilumab-treated (2/68, 2.9%) and placebo-treated (1/39, 2.6%) adolescents reported one or more conjunctivitis event. All events were mild to moderate. One dupilumab-treated patient received treatment for conjunctivitis. All cases recovered/resolved during the study. No patients in these trials discontinued study treatment temporarily or permanently because of conjunctivitis. In ADOL, one case of unspecified viral keratitis (specific viral etiology not known) in the dupilumab 300-mg every 4 weeks group and one case of allergic blepharitis in the placebo group were reported; both events resolved during the treatment period, and neither led to treatment discontinuation.

Conclusions: Dupilumab-treated adolescents in atopic dermatitis trials had a higher incidence of conjunctivitis than placebo-treated patients, whereas overall rates of conjunctivitis among adolescents in the asthma trial were lower than in atopic dermatitis trials and were similar for dupilumab- and placebo-treated patients. Most events were mild to moderate, most recovered/resolved, and none prompted study withdrawal. These results are similar to those reported in adult trials and support a drug-disease interaction. CLINICALTRIALS.

Gov Identifiers: NCT03054428, NCT02612454, NCT02414854. Conjunctivitis in Dupilumab Clinical Trials for Adolescents with Atopic Dermatitis or Asthma (MP4 18453 kb).
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http://dx.doi.org/10.1007/s40257-020-00577-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7847457PMC
January 2021

Dupilumab Improves Asthma and Sinonasal Outcomes in Adults with Moderate to Severe Atopic Dermatitis.

J Allergy Clin Immunol Pract 2021 Mar 13;9(3):1212-1223.e6. Epub 2021 Jan 13.

Regeneron Pharmaceuticals, Inc, Tarrytown, NY.

Background: Dupilumab has demonstrated efficacy with acceptable safety in clinical trials in patients with moderate to severe atopic dermatitis (AD).

Objective: To assess dupilumab's impact on asthma and sinonasal conditions in adult patients with moderate to severe AD in four randomized, double-blinded, placebo-controlled trials.

Methods: In LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02755649), CHRONOS (NCT02260986), and CAFÉ (NCT02755649), patients received placebo, dupilumab 300 mg every 2 weeks (q2w), or dupilumab 300 mg weekly (qw). In CHRONOS and CAFÉ, patients received concomitant topical corticosteroids. This post hoc analysis assessed Asthma Control Questionnaire-5 (ACQ-5) scores in patients with asthma, Sino-Nasal Outcome Test-22 (SNOT-22) scores in patients with sinonasal conditions, and AD signs and symptoms in all patients.

Results: Of the 2444 patients, 463 had asthma with baseline ACQ-5 ≥ 0.5 (19%); 1171 had sinonasal conditions (48%); and 311 had both (13%). At week 16, ACQ-5 scores (least squares mean change from baseline [standard error]) improved by 0.27 (0.07), 0.59 (0.08), and 0.56 (0.07) in placebo-, q2w-, and qw-treated patients with asthma, respectively, whereas SNOT-22 scores improved by 5.1 (0.8), 9.9 (0.9), and 10.8 (0.8) in patients with sinonasal conditions (P < .01 for all dupilumab vs placebo). Improvements in ACQ-5 and SNOT-22 were also seen in patients with both conditions. Dupilumab also significantly improved AD signs and symptoms among all subgroups.

Conclusions: In this first analysis of patients with comorbid moderate to severe AD, asthma, and/or chronic sinonasal conditions, dupilumab improved all three diseases in a clinically meaningful and statistically significant manner (vs placebo), based on validated outcome measures.
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http://dx.doi.org/10.1016/j.jaip.2020.12.059DOI Listing
March 2021

Dupilumab Efficacy in Patients Stratified by Baseline Treatment Intensity and Lung Function.

J Asthma Allergy 2020 16;13:701-711. Epub 2020 Dec 16.

Sanofi, Bridgewater, NJ, USA.

Purpose: The Phase 3 LIBERTY ASTHMA QUEST study in patients aged ≥12 years with uncontrolled, moderate-to-severe asthma demonstrated the efficacy and safety of dupilumab 200 mg and 300 mg every 2 weeks (q2w) vs matched placebo in the overall population. This post hoc analysis assessed dupilumab efficacy by disease severity as evidenced by baseline % predicted forced expiratory volume in 1 second (FEV) and dose of inhaled corticosteroids (ICS).

Patients And Methods: Severe asthma exacerbation rates, change from baseline in FEV, asthma control, quality of life, and fractional exhaled nitric oxide (FeNO) levels over the 52-week treatment period were assessed in patients with elevated type 2 inflammation biomarkers stratified by ICS dose and FEV% predicted at baseline.

Results: In patients with elevated baseline eosinophils, dupilumab 200 mg and 300 mg q2w vs placebo reduced severe exacerbation rates by 50% (=0.06) and 67% (=0.001), respectively, in those with medium-dose ICS/FEV% predicted 60-90%, and by 59% (<0.001) and 47% (=0.006) in those with high-dose ICS/FEV% predicted <60%, improved pre-bronchodilator FEV at Week 12 by 0.16L (=0.005) and 0.08L (=0.13), and by 0.20L (=0.003) and 0.21L (<0.001), respectively, in the same subgroups. Dupilumab vs placebo also improved asthma control and quality of life and suppressed FeNO levels in all patient subgroups with similar results observed irrespective of baseline biomarker status or disease severity.

Conclusion: Dupilumab reduced severe exacerbations and improved lung function, asthma control and quality of life in patients with elevated baseline eosinophils irrespective of baseline ICS dose or FEV% predicted.
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http://dx.doi.org/10.2147/JAA.S275068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751293PMC
December 2020

Efficacy and safety of dupilumab with concomitant topical corticosteroids in children 6 to 11 years old with severe atopic dermatitis: A randomized, double-blinded, placebo-controlled phase 3 trial.

J Am Acad Dermatol 2020 Nov 20;83(5):1282-1293. Epub 2020 Jun 20.

Regeneron Pharmaceuticals, Inc, Tarrytown New York. Electronic address:

Background: Children with severe atopic dermatitis (AD) have limited treatment options.

Objective: We report the efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies.

Methods: In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight <30 kg; 200 mg q2w, baseline weight ≥30 kg), or placebo; with concomitant medium-potency TCS.

Results: Both the q4w and q2w dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children <30 kg and 200 mg q2w in children ≥30 kg. Conjunctivitis and injection-site reactions were more common with dupilumab + TCS than with placebo + TCS.

Limitations: Short-term 16-week treatment period; severe AD only.

Conclusion: Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL.
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http://dx.doi.org/10.1016/j.jaad.2020.06.054DOI Listing
November 2020

Dupilumab Provides Favorable Safety and Sustained Efficacy for up to 3 Years in an Open-Label Study of Adults with Moderate-to-Severe Atopic Dermatitis.

Am J Clin Dermatol 2020 Aug;21(4):567-577

Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd, Tarrytown, NY, 10591, USA.

Background: Management of moderate-to-severe atopic dermatitis (AD) commonly requires long-term treatment.

Objective: The aim of this study was to report the safety and efficacy of dupilumab treatment for up to 3 years in adults with moderate-to-severe AD.

Methods: This ongoing, multicenter, open-label extension study (LIBERTY AD OLE; NCT01949311) assessed dupilumab treatment in adults previously enrolled in dupilumab trials. Patients received dupilumab 300 mg weekly up to 148 weeks. The primary outcome was safety.

Results: Of 2677 patients enrolled and treated, 347 reached week 148. Mean self-reported drug compliance was 98.2%. Safety data were consistent with previously reported trials (270.1 adverse events [AEs]/100 patient-years; 6.9 serious AEs/100 patient-years) and the known dupilumab safety profile. Common AEs (≥ 5% of patients) included nasopharyngitis, AD, upper respiratory tract infection, conjunctivitis, headache, oral herpes, and injection-site reactions. AD signs and symptoms showed sustained improvements during treatment with mean (standard deviation, mean percentage change from parent study baseline) Eczema Area and Severity Index 1.4 (3.2, - 95.4%) and weekly Pruritus Numerical Rating Scale 2.2 (1.8, - 65.4%) at week 148.

Limitations: No control arm; fewer patients at later time points; regimen different from the approved 300 mg every 2 weeks dose.

Conclusion: These safety and efficacy results support dupilumab as a continuous long-term treatment for adults with moderate-to-severe AD.

Trial Registration: ClinicalTrials.gov: NCT01949311. Dupilumab provides favorable safety and sustained efficacy for up to 3 years in an open-label study of adults with moderate-to-severe atopic dermatitis (MP4  139831 kb).
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http://dx.doi.org/10.1007/s40257-020-00527-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371647PMC
August 2020

Efficacy and Safety of Dupilumab in Adolescents With Uncontrolled Moderate to Severe Atopic Dermatitis: A Phase 3 Randomized Clinical Trial.

JAMA Dermatol 2020 01;156(1):44-56

Regeneron Pharmaceuticals Inc, Tarrytown, New York.

Importance: Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population.

Objective: To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD.

Design, Setting, And Participants: A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included.

Interventions: Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85).

Main Outcomes And Measures: Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16.

Results: A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%).

Conclusions And Relevance: In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults.

Trial Registration: ClinicalTrials.gov identifier: NCT03054428.
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http://dx.doi.org/10.1001/jamadermatol.2019.3336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6865265PMC
January 2020

Dupilumab shows long-term safety and efficacy in patients with moderate to severe atopic dermatitis enrolled in a phase 3 open-label extension study.

J Am Acad Dermatol 2020 Feb 30;82(2):377-388. Epub 2019 Jul 30.

Regeneron Pharmaceuticals, Inc, Tarrytown, New York.

Background: Significant unmet need exists for long-term treatment of moderate to severe atopic dermatitis (AD).

Objective: To assess the long-term safety and efficacy of dupilumab in patients with AD.

Methods: This ongoing, multicenter, open-label extension study (NCT01949311) evaluated long-term dupilumab treatment in adults who had previously participated in phase 1 through 3 clinical trials of dupilumab for AD. This analysis examined patients given 300 mg dupilumab weekly for up to 76 weeks at data cutoff (April 2016). Safety was the primary outcome; efficacy was also evaluated.

Results: Of 1491 enrolled patients (1042.9 patient-years), 92.9% were receiving treatment at cutoff. The safety profile was consistent with previously reported trials (420.4 adverse events/100 patient-years and 8.5 serious adverse events/100 patient-years), with no new safety signals; common adverse events included nasopharyngitis, conjunctivitis, and injection-site reactions. Sustained improvement was seen up to 76 weeks in all efficacy outcomes, including measures of skin inflammation, pruritus, and quality of life.

Limitations: Lack of control arm, limited number of patients with 76 weeks or longer of treatment (median follow-up, 24 weeks), and patients not receiving the approved dose regimen of 300 mg every 2 weeks.

Conclusion: The safety and efficacy profile from this study supports the role of dupilumab as continuous long-term treatment for patients with moderate to severe AD.
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http://dx.doi.org/10.1016/j.jaad.2019.07.074DOI Listing
February 2020

Dupilumab Efficacy in Uncontrolled, Moderate-to-Severe Asthma with Self-Reported Chronic Rhinosinusitis.

J Allergy Clin Immunol Pract 2020 02 24;8(2):527-539.e9. Epub 2019 Jul 24.

Sanofi, Bridgewater, NJ.

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for IL-4 and IL-13 signaling, key drivers of type 2 inflammation. In the phase 3 study (NCT02414854), add-on dupilumab 200 mg/300 mg every 2 weeks, versus placebo, significantly reduced severe asthma exacerbations and improved pre-bronchodilator forced expiratory volume in 1 second (FEV) and quality-of-life measures in patients with uncontrolled, moderate-to-severe asthma, with greater efficacy observed in those with a high baseline type 2 phenotype.

Objective: To assess the efficacy and safety of dupilumab in patients with uncontrolled, moderate-to-severe asthma with or without self-reported comorbid chronic rhinosinusitis (CRS or non-CRS).

Methods: Comorbid CRS was self-reported by patients using an e-diary. Annualized severe exacerbation rates, changes from baseline in pre- and post-bronchodilator FEV, patient-reported outcomes, type 2 biomarkers, and safety were assessed.

Results: CRS was self-reported by 382 of 1902 (20.1%) patients. Dupilumab 200 mg/300 mg reduced annualized severe exacerbation rates by 63%/61%, respectively, in patients with CRS, and by 42%/40% in patients without CRS (all P < .001 vs placebo). Dupilumab also improved lung function and patient-reported asthma control and quality of life, and suppressed type 2 biomarkers versus placebo in both subgroups. Clinical responses were rapid, with near-maximal responses observed at the earliest measured time points and sustained at week 52. Improvements observed in the CRS subgroup were similar to or numerically greater than those in the non-CRS subgroup.

Conclusion: Dupilumab showed efficacy and was generally well tolerated in patients with uncontrolled, moderate-to-severe asthma with or without CRS.
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http://dx.doi.org/10.1016/j.jaip.2019.07.016DOI Listing
February 2020

AR101 Oral Immunotherapy for Peanut Allergy.

N Engl J Med 2018 Nov 18;379(21):1991-2001. Epub 2018 Nov 18.

Background: Peanut allergy, for which there are no approved treatment options, affects patients who are at risk for unpredictable and occasionally life-threatening allergic reactions.

Methods: In a phase 3 trial, we screened participants 4 to 55 years of age with peanut allergy for allergic dose-limiting symptoms at a challenge dose of 100 mg or less of peanut protein (approximately one third of a peanut kernel) in a double-blind, placebo-controlled food challenge. Participants with an allergic response were randomly assigned, in a 3:1 ratio, to receive AR101 (a peanut-derived investigational biologic oral immunotherapy drug) or placebo in an escalating-dose program. Participants who completed the regimen (i.e., received 300 mg per day of the maintenance regimen for approximately 24 weeks) underwent a double-blind, placebo-controlled food challenge at trial exit. The primary efficacy end point was the proportion of participants 4 to 17 years of age who could ingest a challenge dose of 600 mg or more, without dose-limiting symptoms.

Results: Of the 551 participants who received AR101 or placebo, 496 were 4 to 17 years of age; of these, 250 of 372 participants (67.2%) who received active treatment, as compared with 5 of 124 participants (4.0%) who received placebo, were able to ingest a dose of 600 mg or more of peanut protein, without dose-limiting symptoms, at the exit food challenge (difference, 63.2 percentage points; 95% confidence interval, 53.0 to 73.3; P<0.001). During the exit food challenge, the maximum severity of symptoms was moderate in 25% of the participants in the active-drug group and 59% of those in the placebo group and severe in 5% and 11%, respectively. Adverse events during the intervention period affected more than 95% of the participants 4 to 17 years of age. A total of 34.7% of the participants in the active-drug group had mild events, as compared with 50.0% of those in the placebo group; 59.7% and 44.4% of the participants, respectively, had events that were graded as moderate, and 4.3% and 0.8%, respectively, had events that were graded as severe. Efficacy was not shown in the participants 18 years of age or older.

Conclusions: In this phase 3 trial of oral immunotherapy in children and adolescents who were highly allergic to peanut, treatment with AR101 resulted in higher doses of peanut protein that could be ingested without dose-limiting symptoms and in lower symptom severity during peanut exposure at the exit food challenge than placebo. (Funded by Aimmune Therapeutics; PALISADE ClinicalTrials.gov number, NCT02635776 .).
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http://dx.doi.org/10.1056/NEJMoa1812856DOI Listing
November 2018

Efficacy, safety, and dose response of glycopyrronium administered by metered dose inhaler using co-suspension delivery technology in subjects with intermittent or mild-to-moderate persistent asthma: A randomized controlled trial.

Respir Med 2018 06 19;139:39-47. Epub 2018 Apr 19.

Pearl - a member of the AstraZeneca Group, Durham, NC, USA.

Objectives: This randomized, double-blind, placebo-controlled, cross-over, Phase II dose-ranging study investigated the efficacy and safety of GP MDI (glycopyrronium administered by metered dose inhaler formulated using co-suspension delivery technology) compared with an open-label active comparator, salmeterol dry powder inhaler (SAL DPI), in subjects with intermittent or mild-to-moderate persistent asthma.

Methods: Subjects were randomized to receive five of seven treatments (GP MDI 28.8, 14.4, 7.2, 3.6, and 1.9 μg, placebo MDI, and SAL DPI 50 μg), each for a 14-day period. The primary endpoint was peak change from baseline in forced expiratory volume in 1 s (FEV) on Day 15. Secondary endpoints included additional lung function parameters and symptoms (Asthma Control Questionnaire-5). Safety was monitored throughout.

Results: Of 248 subjects randomized, 211 completed the study. All doses of GP MDI resulted in significant improvements in the primary endpoint compared with placebo MDI in a dose-ordered fashion (range 85-155 mL, p < .0001), without appreciable differences between the two highest doses of GP MDI (28.8 and 14.4 μg) and SAL DPI 50 μg. Improvements in secondary lung function endpoints and symptoms were generally dose-ordered, with GP MDI 28.8 μg showing the greatest improvements. Similar results were observed when endpoints were analyzed based on subjects' background use of inhaled corticosteroids (yes/no). All GP MDI doses were well tolerated with no evidence of a dose-related effect on adverse events.

Conclusions: The results of this study suggest that GP MDI could offer an important treatment option for maintenance therapy of asthma, and warrants further investigation in Phase III clinical trials.
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http://dx.doi.org/10.1016/j.rmed.2018.04.013DOI Listing
June 2018

Efficacy and Safety of Dupilumab in Glucocorticoid-Dependent Severe Asthma.

N Engl J Med 2018 06 21;378(26):2475-2485. Epub 2018 May 21.

From LungenClinic Grosshansdorf, Grosshansdorf, and Christian Albrechts University Kiel, Kiel - both in Germany (K.F.R.); McMaster University and St. Joseph's Healthcare, Hamilton, ON, Canada (P.N.); Ghent University Hospital, Ghent, Belgium (G.B.); Fundación CIDEA (Centro de Investigación de Enfermedades Alérgicas y Respiratorias), Buenos Aires (J.F.M.); Washington University School of Medicine, St. Louis (M.C.); Peninsula Research Associates, Rolling Hills Estates, CA (L.S.); Sanofi, Bridgewater, NJ (H.Z., B.N.S., H.S., G.P., C.A., A.T.); Regeneron Pharmaceuticals, Tarrytown, NY (J.D.H., J.C., N.A., M.R., B.A., N.M.H.G., N.S., G.D.Y.); and Sanofi, Chilly Mazarin, France (A.K.).

Background: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. Its effectiveness in reducing oral glucocorticoid use in patients with severe asthma while maintaining asthma control is unknown.

Methods: We randomly assigned 210 patients with oral glucocorticoid-treated asthma to receive add-on dupilumab (at a dose of 300 mg) or placebo every 2 weeks for 24 weeks. After a glucocorticoid dose-adjustment period before randomization, glucocorticoid doses were adjusted in a downward trend from week 4 to week 20 and then maintained at a stable dose for 4 weeks. The primary end point was the percentage reduction in the glucocorticoid dose at week 24. Key secondary end points were the proportion of patients at week 24 with a reduction of at least 50% in the glucocorticoid dose and the proportion of patients with a reduction to a glucocorticoid dose of less than 5 mg per day. Severe exacerbation rates and the forced expiratory volume in 1 second (FEV) before bronchodilator use were also assessed.

Results: The percentage change in the glucocorticoid dose was -70.1% in the dupilumab group, as compared with -41.9% in the placebo group (P<0.001); 80% versus 50% of the patients had a dose reduction of at least 50%, 69% versus 33% had a dose reduction to less than 5 mg per day, and 48% versus 25% completely discontinued oral glucocorticoid use. Despite reductions in the glucocorticoid dose, in the overall population, dupilumab treatment resulted in a severe exacerbation rate that was 59% (95% confidence interval [CI], 37 to 74) lower than that in the placebo group and resulted in an FEV that was 0.22 liters (95% CI, 0.09 to 0.34) higher. Injection-site reactions were more common with dupilumab than with placebo (9% vs. 4%). Transient blood eosinophilia was observed in more patients in the dupilumab group than in the placebo group (14% vs. 1%).

Conclusions: In patients with glucocorticoid-dependent severe asthma, dupilumab treatment reduced oral glucocorticoid use while decreasing the rate of severe exacerbations and increasing the FEV. Transient eosinophilia was observed in approximately 1 in 7 dupilumab-treated patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA VENTURE ClinicalTrials.gov number, NCT02528214 .).
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http://dx.doi.org/10.1056/NEJMoa1804093DOI Listing
June 2018

Dupilumab Efficacy and Safety in Moderate-to-Severe Uncontrolled Asthma.

N Engl J Med 2018 06 21;378(26):2486-2496. Epub 2018 May 21.

From the Washington University School of Medicine, St. Louis (M.C.); David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles (J. Corren), and Peninsula Research Associates, Rolling Hills Estates (L.S.) - both in California; Oxford Respiratory National Institute for Health Research Biomedical Research Centre, University of Oxford, Oxford, United Kingdom (I.D.P.); Fundación CIDEA (Centro de Investigación de Enfermedades Alérgicas y Respiratorias), Buenos Aires (J.M.); the University of Pittsburgh Asthma Institute, University of Pittsburgh, Pittsburgh (S.W.); LungenClinic Grosshansdorf, Grosshansdorf, and Christian Albrechts University Kiel, Kiel - both in Germany (K.F.R.); the Division of Allergy, Pulmonary, and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison (W.W.B.); the Asthma and Allergy Center, Bellevue, NE (L.F.); the University of British Columbia, Vancouver, Canada (J.M.F.); Campbelltown Hospital and Western Sydney University, Sydney (C.K.); the Faculty of Medicine, Kindai University, Osakasayama, Japan (Y.T.); Sanofi, Bridgewater, NJ (B.Z., H.S., G.P., B.N.S., A.T.); Regeneron Pharmaceuticals, Tarrytown, NY (N.A., M.R., B.A., J. Chao, N.M.H.G., J.D.H., N.S., G.D.Y.); Sanofi, Chilly-Mazarin, France (A.K.); and Sanofi, Prague, Czech Republic (R.M.).

Background: Dupilumab is a fully human anti-interleukin-4 receptor α monoclonal antibody that blocks both interleukin-4 and interleukin-13 signaling. We assessed its efficacy and safety in patients with uncontrolled asthma.

Methods: We randomly assigned 1902 patients 12 years of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at a dose of 200 or 300 mg every 2 weeks or matched-volume placebos for 52 weeks. The primary end points were the annualized rate of severe asthma exacerbations and the absolute change from baseline to week 12 in the forced expiratory volume in 1 second (FEV) before bronchodilator use in the overall trial population. Secondary end points included the exacerbation rate and FEV in patients with a blood eosinophil count of 300 or more per cubic millimeter. Asthma control and dupilumab safety were also assessed.

Results: The annualized rate of severe asthma exacerbations was 0.46 (95% confidence interval [CI], 0.39 to 0.53) among patients assigned to 200 mg of dupilumab every 2 weeks and 0.87 (95% CI, 0.72 to 1.05) among those assigned to a matched placebo, for a 47.7% lower rate with dupilumab than with placebo (P<0.001); similar results were seen with the dupilumab dose of 300 mg every 2 weeks. At week 12, the FEV had increased by 0.32 liters in patients assigned to the lower dose of dupilumab (difference vs. matched placebo, 0.14 liters; P<0.001); similar results were seen with the higher dose. Among patients with a blood eosinophil count of 300 or more per cubic millimeter, the annualized rate of severe asthma exacerbations was 0.37 (95% CI, 0.29 to 0.48) among those receiving lower-dose dupilumab and 1.08 (95% CI, 0.85 to 1.38) among those receiving a matched placebo (65.8% lower rate with dupilumab than with placebo; 95% CI, 52.0 to 75.6); similar results were observed with the higher dose. Blood eosinophilia occurred after the start of the intervention in 52 patients (4.1%) who received dupilumab as compared with 4 patients (0.6%) who received placebo.

Conclusions: In this trial, patients who received dupilumab had significantly lower rates of severe asthma exacerbation than those who received placebo, as well as better lung function and asthma control. Greater benefits were seen in patients with higher baseline levels of eosinophils. Hypereosinophilia was observed in some patients. (Funded by Sanofi and Regeneron Pharmaceuticals; LIBERTY ASTHMA QUEST ClinicalTrials.gov number, NCT02414854 .).
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http://dx.doi.org/10.1056/NEJMoa1804092DOI Listing
June 2018

Fluticasone propionate and fluticasone propionate/salmeterol multidose dry powder inhalers compared with placebo for persistent asthma.

Allergy Asthma Proc 2017 09 21;38(5):343-353. Epub 2017 Jun 21.

Background: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) has been developed, which allows for lower doses of fluticasone propionate (Fp) and Fp/salmeterol (FS) for the treatment of patients with asthma.

Objective: This phase III, multicenter, double-blind, parallel-group study (NCT02141854) evaluated the efficacy and safety of Fp MDPI and FS MDPI versus placebo MDPI.

Methods: Patients aged ≥12 years with persistent asthma who previously took an inhaled corticosteroid with or without a long-acting beta-agonist entered a 14- to 21-day run-in period, during which they received single-blind, low-dose Fp MDPI 50 μg (1 inhalation twice daily [b.i.d.]) and used albuterol hydrofluoroalkane (HFA) metered-dose inhaler (MDI) for rescue. The patients who continued to meet eligibility criteria (N = 728) were randomized to Fp MDPI (100 or 200 μg), FS MDPI (100 μg/12.5 μg or 200 μg/12.5 μg), or placebo (1 inhalation b.i.d.). Primary efficacy end points were the change from baseline in forced expiratory volume in 1 second (FEV1) and the baseline-adjusted area under the FEV1 curve 12 hours after the dose at week 12. Secondary efficacy end points were A.M. peak expiratory flow, asthma symptom scores, albuterol HFA MDI use, time to patient withdrawal, Asthma Quality of Life scores, and time to 15% and 12% improvement from baseline in FEV1. Safety end points were monitored.

Results: Fp MDPI and FS MDPI significantly improved both primary end points compared with placebo (p < 0.05). FS MDPI significantly improved both end points versus the corresponding Fp MDPI dose (p < 0.05), with improvement also greater for FS MDPI 100 μg/12.5 μg versus Fp MDPI 200 μg (p < 0.05). Both active treatments improved a variety of secondary end points and exhibited a safety profile consistent with the drug classes.

Conclusion: Delivery of Fp and FS via the novel MDPI provided significant clinical benefits and was well tolerated in patients with persistent asthma.
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http://dx.doi.org/10.2500/aap.2017.38.4069DOI Listing
September 2017

American Academy of Asthma, Allergy & Immunology membership experience with venom immunotherapy in chronic medical conditions and pregnancy, and in young children.

Allergy Asthma Proc 2017 Mar;38(2):121-129

Background: Few data exist regarding the use of venom immunotherapy (VIT) in specific high-risk chronic medical conditions and pregnancy, and in young children.

Methods: A Web-based survey was sent to American Academy of Asthma Allergy & Immunology members to explore their VIT experience in potential high-risk medical conditions and pregnancy, and in young children. Major problems were defined as "activation of underlying disease and/or VIT not well tolerated (systemic adverse events) and/or VIT discontinued for medical reasons." Results were expressed descriptively.

Results: A total of 697 of 5123 surveys (14%) were completed: 87% of the respondents were based in the United States, and 28% worked in an academic setting. Most respondents (71%) believed that pregnancy was a contraindication for starting VIT. Most were comfortable continuing VIT (51%) if the woman became pregnant after starting therapy. Of the allergists who treated children, many would give VIT down to age 5 years (42%) or younger, ages 1-4 years (35%). The following list is of the specific medical condition, the number of allergists who used VIT in patients with this condition, and the percentage who reported major problems: severe asthma, 212 (4.2%); hypertension, 287 (1.1%); coronary artery disease, 222 (3.6%); arrhythmias, 136 (3.4%); cerebrovascular disease, 104 (5.1%); cancer in remission, 166 (0%); cancer stable but still under treatment, 44 (7.2%); a history of bone marrow transplantation, 15 (4.9%); a history of solid organ transplantation, 29 (3.6%); human immunodeficiency virus, 53 (1.4%); acquired immunodeficiency syndrome, 24 (6.2%); stable autoimmune disease, 164 (2.8%); mastocytosis, 66 (18.4%); elevated serum tryptase, 101 (10.8%); immunodeficiency 59 (2.5%).

Conclusion: Many allergists were comfortable using VIT in young children and continuing but not starting pregnant women on VIT. VIT was commonly used in patients with hypertension, coronary artery disease, arrhythmias, cancer in remission, and stable autoimmune disease. Major problems were most frequently reported in use with mastocytosis, elevated tryptase, and cancer still under treatment.
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http://dx.doi.org/10.2500/aap.2017.38.4024DOI Listing
March 2017

American Academy of Allergy, Asthma & Immunology membership experience with allergen immunotherapy safety in patients with specific medical conditions.

Allergy Asthma Proc 2016 Sep;37(5):112-22

Hospital Médica Sur, Mexico City, Mexico.

Background: Little data in the literature exist concerning patients with certain underlying medical conditions who receive allergen subcutaneous immunotherapy (SCIT).

Objective: To survey allergists' experience with SCIT in patients with medical conditions considered to impose an elevated risk for untoward outcomes.

Methods: A Web-based survey was conducted among members of the American Academy of Allergy, Asthma & Immunology to query about their experience with SCIT in patients with certain medical conditions.

Results: There were 1085 replies (21% response), of whom, 86% were U.S. based, 51% were suburban, 31% were academic, 42% were medium-sized practices, and 54% had >15 years' experience. In responders' opinion, SCIT was "contraindicated" in patients with the following: acquired immune deficiency syndrome (AIDS) (48%), cancer (and still receiving active treatment) (33%), severe asthma (32%), and a history of transplantation (30%). Even so, survey responders collectively gave SCIT to >2400 patients for each of these conditions: severe asthma, coronary artery disease, cancer in remission, and autoimmune disorders; and to ≥5400 patients with hypertension and ≥4100 women who became pregnant. The experience of colleagues with these patients rarely resulted in major problems (i.e., activation of underlying disease, systemic reactions to SCIT, or SCIT discontinuation), with the exception of severe asthma (12.5%), initiation of SCIT during pregnancy (5.4%), and AIDS (4.2%). For most other conditions, it was ≤1.5% (e.g., continue during pregnancy, cancer in remission, history of transplantation, positive human immunodeficiency virus and no AIDS).

Conclusion: According to the experience of a large group of practicing allergists, the American Academy of Allergy, Asthma & Immunology members, few medical conditions seemed to pose an elevated risk for untoward outcomes from SCIT. Because these are survey results, prospective research might yield even more solid data.
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http://dx.doi.org/10.2500/aap.2016.37.3981DOI Listing
September 2016

Dupilumab in persistent asthma with elevated eosinophil levels.

N Engl J Med 2013 Jun 21;368(26):2455-66. Epub 2013 May 21.

Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA.

Background: Moderate-to-severe asthma remains poorly treated. We evaluated the efficacy and safety of dupilumab (SAR231893/REGN668), a fully human monoclonal antibody to the alpha subunit of the interleukin-4 receptor, in patients with persistent, moderate-to-severe asthma and elevated eosinophil levels.

Methods: We enrolled patients with persistent, moderate-to-severe asthma and a blood eosinophil count of at least 300 cells per microliter or a sputum eosinophil level of at least 3% who used medium-dose to high-dose inhaled glucocorticoids plus long-acting beta-agonists (LABAs). We administered dupilumab (300 mg) or placebo subcutaneously once weekly. Patients were instructed to discontinue LABAs at week 4 and to taper and discontinue inhaled glucocorticoids during weeks 6 through 9. Patients received the study drug for 12 weeks or until a protocol-defined asthma exacerbation occurred. The primary end point was the occurrence of an asthma exacerbation; secondary end points included a range of measures of asthma control. Effects on various type 2 helper T-cell (Th2)-associated biomarkers and safety and tolerability were also evaluated.

Results: A total of 52 patients were assigned to the dupilumab group, and 52 patients were assigned to the placebo group. Baseline characteristics were similar in the two groups. Three patients had an asthma exacerbation with dupilumab (6%) versus 23 with placebo (44%), corresponding to an 87% reduction with dupilumab (odds ratio, 0.08; 95% confidence interval, 0.02 to 0.28; P<0.001). Significant improvements were observed for most measures of lung function and asthma control. Dupilumab reduced biomarkers associated with Th2-driven inflammation. Injection-site reactions, nasopharyngitis, nausea, and headache occurred more frequently with dupilumab than with placebo.

Conclusions: In patients with persistent, moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, as compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, with improved lung function and reduced levels of Th2-associated inflammatory markers. (Funded by Sanofi and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT01312961.).
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http://dx.doi.org/10.1056/NEJMoa1304048DOI Listing
June 2013

Pharmacokinetics and pharmacodynamics of gatifloxacin in children with recurrent otitis media: application of sparse sampling in clinical development.

Diagn Microbiol Infect Dis 2007 Sep;59(1):67-74

Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, NY 12206, USA.

Gatifloxacin is a 4th-generation fluoroquinolone previously under investigation for the treatment of otitis media in infants and children. These analyses were designed to evaluate the extent of drug exposure relative to adult populations and to examine the relationship between drug exposure and response to therapy in children with recurrent otitis media or early treatment failures of acute otitis media. The patient population included 187 patients from an open-label, multicenter, noncomparative study using gatifloxacin 10 mg/kg once daily. Gatifloxacin exposure was estimated using a single steady-state blood sample in conjunction with a pharmacostatistical model developed using a separate pediatric data set. Gatifloxacin exposure was equivalent to that in adults given 400 mg daily. Of the 41 patients who had Streptococcus pneumoniae from middle ear culture, there were only 3 bacteriologic failures; there was no relationship between plasma fu AUC(0-24):MIC ratio and outcome. In conclusion, population pharmacokinetic/pharmacodynamic methods allowed estimation of drug exposure using one sample per patient.
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http://dx.doi.org/10.1016/j.diagmicrobio.2007.04.015DOI Listing
September 2007

Randomized, investigator-blinded, multicenter, comparative study of gatifloxacin versus amoxicillin/clavulanate in recurrent otitis media and acute otitis media treatment failure in children.

Pediatr Infect Dis J 2005 Apr;24(4):301-8

Peninsula Research Associates, Rolling Hills Estates, CA, USA.

Background: Recurrent otitis media and acute otitis media treatment failure are commonly encountered in the pediatric population.

Objective: To compare the clinical efficacy of gatifloxacin with amoxicillin/clavulanate for the treatment of acute otitis media treatment failure and recurrent otitis media.

Methods: Three hundred fifty-four children 6 months-7 years with recurrent otitis media and/or acute otitis media failure were stratified according to age (younger than 2 years versus 2 years or older) and then randomly assigned to 10 days of treatment with gatifloxacin 10 mg/kg once daily or amoxicillin/clavulanate 90 mg/6.4 mg in 2 divided doses. Tympanocentesis was performed in 116 children with acute otitis media treatment failure and 52 with recurrent otitis media at study entry to validate the clinical diagnosis and provide microbiologic data. The primary outcome measure was clinical resolution of infection at the test-of-cure visit 3-10 days after completing treatment.

Results: Clinical resolution of acute otitis media was observed in 79.0% (49 of 62) of clinically evaluable children younger than 2 years and 90.3% (56 of 62) of those 2 years or older who were treated with gatifloxacin as compared with 77.6% (45 of 58) of children younger than 2 years and 79.7% (47 of 59) of children 2 years or older treated with amoxicillin/clavulanate. In patients with acute otitis media treatment failure, clinical response rates for children younger than 2 years and those 2 years or older were 87.5% (21 of 24) and 97.0% (32 of 33) with gatifloxacin versus 63.6% (14 of 22) and 83.9% (26 of 31) with amoxicillin/clavulanate. The corresponding clinical response rates in patients with recurrent otitis media were 79.2% (19 of 24) and 85.7% (18 of 21) with gatifloxacin and 90.5% (19 of 21) and 76.0% (19 of 25) with amoxicillin/clavulanate. Clinical success in those subjects having pretreatment middle ear fluid pathogens was similar for the 2 regimens [80.0% (24 of 30) gatifloxacin, 77.1% (27 of 35) amoxicillin/clavulanate]. Emergence of fluoroquinolone-resistant strains was not observed. Both drugs were generally well-tolerated. Diarrhea was the most common drug-related adverse event (10% gatifloxacin, 18% amoxicillin/clavulanate). No evidence of abnormal joint or gait findings was found during a 12-month follow-up.

Conclusions: Gatifloxacin once daily is at least as effective and well-tolerated as amoxicillin/clavulanate twice daily in children with acute otitis media treatment failure or recurrent otitis media. There was no evidence of arthrotoxicity or emergence of fluoroquinolone-resistant bacteria in gatifloxacin-treated children.
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http://dx.doi.org/10.1097/01.inf.0000157084.35865.baDOI Listing
April 2005

Community-based treatment of acute uncomplicated bacterial rhinosinusitis with gatifloxacin.

Otolaryngol Head Neck Surg 2002 Sep;127(3):182-9

Peninsula Research Associates, Rolling Hills Estates, CA 90274, USA.

Objective: We sought to evaluate gatifloxacin in adults with acute uncomplicated bacterial rhinosinusitis.

Study Design: TeqCES was an open-label, multicenter, noncomparative study of the safety and efficacy of gatifloxacin. More than 11,000 adult patients with acute uncomplicated rhinosinusitis received gatifloxacin 400 mg once daily for 10 days.

Results: Moraxella catarrhalis (91% beta-lactamase producers), Haemophilus influenzae (28% beta-lactamase producers), Streptococcus pneumoniae (18% intermediately resistant and 14% fully resistant to penicillin), and Staphylococcus aureus were the predominant pathogens isolated from purulent nasal discharge. More than 99% of rhinosinusitis pathogens isolated from the nasopharynx of patients meeting the clinical criteria for rhinosinusitis were susceptible to gatifloxacin. Among 10,353 patients whose clinical response could be determined, 91.6% were cured. Clinical cure rates exceeded 90% for the major pathogens. Gatifloxacin was well tolerated; drug-related adverse events that occurred in 1% or more of patients were nausea (4.4%), dizziness (1.8%), diarrhea (1.4%), and headache (1.0%).

Conclusion: Gatifloxacin is effective for patients with acute bacterial rhinosinusitis in the community.
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http://dx.doi.org/10.1067/mhn.2002.127590DOI Listing
September 2002

A multicenter, randomized, investigator-blinded study of 5- and 10-day gatifloxacin versus 10-day amoxicillin/clavulanate in patients with acute bacterial sinusitis.

Clin Ther 2002 Feb;24(2):269-81

Peninsula Research Associates, Rolling Hills Estates, California 90274, USA.

Background: Treatment guidelines for acute bacterial sinusitis recommend 10 to 14 days of therapy with amoxicillin/clavulanate, high-dose amoxicillin, cefpodoxime, cefuroxime, or a newer fluoroquinolone.

Objective: This study compared the clinical efficacy of short-course (5-day) gatifloxacin with standard 10-day regimens of amoxicillin/clavulanate or gatifloxacin in patients with a diagnosis of acute, uncomplicated maxillary sinusitis.

Methods: This was a multicenter, investigator-blinded study in adult patients (age >18 years) with physical findings, signs and symptoms (for at least 7 days), and radiographic findings indicating acute, uncomplicated maxillary sinusitis. Patients were randomized to receive gatifloxacin 400 mg once daily for 5 days, gatifloxacin 400 mg once daily for 10 days, or amoxicillin/clavulanate 875 mg twice daily for 10 days. Clinical response was assessed once between days 3 and 5 of treatment, once I to 3 days after the completion of study treatment, once 7 to 14 days posttreatment (test-of-cure visit), and once 21 to 28 days posttreatment. Safety was assessed throughout the study.

Results: The study enrolled 445 patients. The treatment groups were similar in terms of history of sinusitis, presenting signs and symptoms, and radiographic findings. The most common presenting symptoms were nasal congestion, sinus tenderness, and purulent nasal discharge (>90% of patients); 99% of patients had abnormal radiographic findings. At the test-of-cure visit, clinical cure rates for clinically evaluable patients in the 3 treatment groups were 74% (102/137) for 5-day gatifloxacin, 80% (101/127) for 10-day gatifloxacin, and 72% (101/ 141) for 10-day amoxicillin/clavulanate (95% CI for the difference in cure rates: 5-day gatifloxacin vs amoxicillin/clavulanate, -7.6 to 13.2; 5- vs 10-day gatifloxacin, -15.2 to 5.1; 10-day gatifloxacin vs amoxicillin/clavulanate, -2.3 to 18.1). The distribution and incidence of drug-related adverse events (AEs) were comparable between treatment groups, and the majority (>95%) were mild or moderate in severity. The most common drug-related AEs included vaginitis, diarrhea, and nausea.

Conclusion: In this population of patients with acute, uncomplicated sinusitis of presumed bacterial origin, a short course (5 days) of gatifloxacin therapy was associated with comparable clinical cure rates and tolerability to those of standard 10-day therapy with gatifloxacin or amoxicillin/clavulanate.
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http://dx.doi.org/10.1016/s0149-2918(02)85023-8DOI Listing
February 2002