MANTA and MANTA-RAy: Rationale and Design of Trials Evaluating Effects of Filgotinib on Semen Parameters in Patients with Inflammatory Diseases.

INTRODUCTION: The phase 2 MANTA and MANTA-RAy studies were developed in consultation with global regulatory authorities to investigate potential impacts of filgotinib, a Janus kinase 1 preferential inhibitor, on semen parameters in men with active inflammatory diseases. Here we describe the methods and rationale for these studies. METHODS AND RATIONALE: The MANTA and MANTA-RAy studies included men (aged 21-65 years) with active inflammatory bowel disease (IBD) and rheumatic diseases, respectively. Participants had no history of reproductive health issues, and the following semen parameter values (≥ 5th percentile of World Health Organization reference values) at baseline: semen volume ≥ 1.5 mL, total sperm/ejaculate ≥ 39 million, sperm concentration ≥ 15 million/mL, sperm total motility ≥ 40% and normal sperm morphology ≥ 30%. Each trial included a 13-week, randomized, double-blind, placebo-controlled period (filgotinib 200 mg vs placebo, up to N = 125 per arm), for pooled analysis of the week-13 primary endpoint (proportion of participants with ≥ 50% decrease from baseline in sperm concentration). All semen assessments were based on two samples (≤ 14 days apart) to minimize effects of physiological variation; stringent standardization processes were applied across assessment sites. From week 13, MANTA and MANTA-RAy study designs deviated owing to disease-specific considerations. All subjects with a ≥ 50% decrease in sperm parameters continued the study in the monitoring phase until reversibility, or up to a maximum of 52 weeks, with standard of care as treatment. Overall conclusions from MANTA and MANTA-RAy will be based on the totality of the data, including secondary/exploratory measures (e.g. sperm motility/morphology, sex hormones, reversibility of any effects on semen parameters). CONCLUSIONS: Despite the complexities, the MANTA and MANTA-RAy studies form a robust trial programme that is the first large-scale, placebo-controlled evaluation of potential impacts of an advanced IBD and rheumatic disease therapy on semen parameters. TRIAL REGISTRATION: EudraCT numbers 2017-000402-38 and 2018-003933-14; ClinicalTrials.gov identifiers NCT03201445 and NCT03926195.

Filgotinib is a treatment for patients with ulcerative colitis and rheumatoid arthritis, and is being studied in other inflammatory diseases. Filgotinib works by blocking Janus kinase 1, an intracellular protein involved in inflammatory signalling processes. We designed the MANTA and MANTA-RAy trials with global health agencies to find out if filgotinib decreases the quality of semen in men with active inflammatory bowel disease (ulcerative colitis or Crohn's disease) (MANTA) or rheumatic disease (rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis or non-radiographic axial spondylitis) (MANTA-RAy). This paper describes the design of the two trials.Patients had normal sperm measurements and could not have had previous reproductive health issues. Nearly 250 patients were included in each trial. In both MANTA and MANTA-RAy, half of the patients were treated with 200 mg of filgotinib once a day for 13 weeks, and the other half with placebo. We determined if any patients had a decrease in number of sperm cells per millilitre (sperm concentration) by at least half after 13 weeks of treatment. We then monitored any patients who had such a decrease in sperm concentration for up to 52 weeks (while they received standard of care treatment) or until the decrease was reversed.The conclusions from the trials will be in a different paper and will be based on all the final data, including changes in sex hormones. This is the first large-scale clinical trial programme to measure the effect of a treatment on sperm in men with inflammatory bowel disease or rheumatic diseases.

Impact of filgotinib on sacroiliac joint magnetic resonance imaging structural lesions at 12 weeks in patients with active ankylosing spondylitis (TORTUGA trial).

OBJECTIVE: To assess the effect of filgotinib, which preferentially inhibits Janus kinase 1 (JAK1), on MRI measures of structural change in the SI joint in patients with active AS in the TORTUGA trial. METHODS: Adults with active AS and inadequate response/intolerance to two or more NSAIDs were randomized 1:1 to filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, T1-weighted MRI scans of the SI joint were evaluated by two independent readers using Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Structural Score (SSS) definitions for erosion, backfill, fat metaplasia and ankylosis. Correlations between SPARCC SSS and improvement in clinical outcomes were also assessed. RESULTS: MRI scans from 87 patients (48 filgotinib, 39 placebo) were evaluated. At baseline there were no notable differences between filgotinib and placebo for any MRI structural lesion types. From baseline to week 12, filgotinib was associated with a significant reduction in SI joint erosion score (P = 0.02) and an increase in backfill score (P = 0.005) vs placebo, with no significant between-group differences for ankylosis (P = 0.46) or fat metaplasia (P = 0.17). At week 12, the change in SPARCC MRI SI joint inflammation scores correlated positively with erosion scores but negatively with backfill scores. CONCLUSION: The significant changes in MRI structural lesions induced by filgotinib in the SI joint by week 12 demonstrate that tissue repair can be observed very soon after starting treatment with a JAK1 preferential inhibitor. This could have prognostic implications for development of ankylosis. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT03117270.

Filgotinib decreases both vertebral body and posterolateral spine inflammation in ankylosing spondylitis: results from the TORTUGA trial.

OBJECTIVES: To assess the effects of filgotinib on inflammatory and structural changes at various spinal locations, based on MRI measures in patients with active AS in the TORTUGA trial. METHODS: In the TORTUGA trial, patients with AS received filgotinib 200 mg (n = 58) or placebo (n = 58) once daily for 12 weeks. In this post hoc analysis, spine MRIs were evaluated using the Canada-Denmark (CANDEN) MRI scoring system to assess changes from baseline to week 12 in total spine and subscores for inflammation, fat, erosion and new bone formation (NBF) at various anatomical locations. Correlations were assessed between CANDEN inflammation and clinical outcomes and Spondyloarthritis Research Consortium of Canada (SPARCC) MRI scores and between baseline CANDEN NBF and baseline BASFI and BASMI scores. RESULTS: MRIs from 47 filgotinib- and 41 placebo-treated patients were evaluated. There were significantly larger reductions with filgotinib vs placebo in total spine inflammation score and most inflammation subscores, including posterolateral elements (costovertebral joints, transverse/spinous processes, soft tissues), facet joints and vertebral bodies. No significant differences were observed for corner or non-corner vertebral body inflammation subscores, spine fat lesion, bone erosion or NBF scores. In the filgotinib group, the change from baseline in the total inflammation score correlated positively with the SPARCC spine score. Baseline NBF scores correlated with baseline BASMI but not BASFI scores. CONCLUSIONS: Compared with placebo, filgotinib treatment was associated with significant reductions in MRI measures of spinal inflammation, including in vertebral bodies, facet joints and posterolateral elements. TRIAL REGISTRATION: ClinicalTrials.gov (https://clinicaltrials.gov), NCT03117270.

Comparison of three quantitative HCV RNA assays in samples from HCV genotype 1- or 4-infected patients treated with the NS3/4A protease inhibitor simeprevir.

BACKGROUND: Monitoring HCV RNA levels during treatment is an important tool for managing protease-inhibitor-based regimens, and different assays used in clinical practice can impact treatment decisions. OBJECTIVES: The concordance of three HCV RNA assays was determined, and their impact on treatment decisions assessed using samples from HCV genotype (GT) 1- and GT4-infected patients treated with the NS3/4A inhibitor simeprevir in combination with pegylated interferon-α/ribavirin. STUDY DESIGN: Plasma samples collected during the simeprevir Phase III studies QUEST-1 and QUEST-2 (GT1), and RESTORE (GT4) were analyzed with the Roche High-Pure-System COBAS(®) TaqMan(®) HCV v2.0 (HPS), the Roche AmpliPrep COBAS(®) TaqMan(®) HCV v2.0 (CAP), and the Abbott RealTime HCV (ART) assay. RESULTS: In GT1, of the 440 samples, 81% were undetectable (rapid virological response; RVR) by HPS at Week 4, 76% by CAP and 44% by ART. In GT4 (103 samples), RVR rates were 67% by HPS and 24% by ART. HCV RNA <25IU/mL at Week 4 was observed for 95-96% and 92% GT1 samples and 86% and 74% GT4 samples by HPS/CAP and ART, respectively. At Week 12, assay concordance for undetectability was high in GT1 and GT4, (95-98% and 93%, respectively). CONCLUSIONS: While different HCV RNA assays can lead to substantially different RVR rates, a good concordance was observed with a cut-off of 25IU/mL. Sustained virologic response rates among GT1 patients achieving RVR or <25IU/mL at Week 4 were high and similar between assays used. At later time points, when viremia is low, assay concordance was high.

Fatigue during treatment for hepatitis C virus: results of self-reported fatigue severity in two Phase IIb studies of simeprevir treatment in patients with hepatitis C virus genotype 1 infection.

BACKGROUND: Fatigue is a common symptom of chronic hepatitis C virus (HCV) infection and a frequent side-effect of peginterferon/ribavirin (PR) therapy for HCV. This study evaluated the impact of adding the oral HCV NS3/4A protease inhibitor simeprevir to PR on patient-reported fatigue and health status among patients with chronic HCV genotype 1 infection enrolled in the Phase IIb PILLAR and ASPIRE trials [NCT00882908; NCT00980330]. METHODS: Treatment-naïve patients (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) were randomized to simeprevir plus PR (simeprevir/PR) or placebo plus PR (placebo/PR). In PILLAR, duration of PR treatment in the simeprevir/PR groups was determined using response-guided therapy (RGT) criteria. PR could be terminated at Week 24, instead of Week 48, if HCV RNA was <25 IU/mL by Week 4 and then undetectable at Weeks 12, 16, and 20. In both studies, patients completed the Fatigue Severity Scale (FSS) and EQ-5D quality-of-life questionnaire in their native language at baseline and throughout the studies up until Week 72. RESULTS: During the first 24 weeks of treatment, mean FSS total score was increased to a similar degree compared with baseline among patients receiving simeprevir/PR or placebo/PR in both studies indicating increased fatigue severity. Mean FSS scores returned to values comparable with baseline among patients receiving simeprevir/PR after Week 24 in PILLAR (after treatment completion for the majority of patients) and in ASPIRE (after Week 48), consistent with RGT enabling early termination of all treatment at Week 24 in 82.2% of simeprevir/PR-treated patients in the PILLAR study. Similar results were observed for EQ-5D, with simeprevir/PR-treated patients experiencing less time with worse health problems according to EQ-5D scores compared with placebo/PR groups in both studies, and more rapid improvement in health status associated with shorter treatment duration in the PILLAR study. CONCLUSIONS: Combination of simeprevir with PR did not increase patient-reported fatigue severity or health status impairments beyond that reported by patients treated with PR alone. Many patients treated with simeprevir/PR returned to pretreatment fatigue and health status levels sooner due to increased treatment efficacy that enabled shorter duration of all therapy, compared with PR alone.

Validation of the Fatigue Severity Scale in chronic hepatitis C.

BACKGROUND: Fatigue is a common symptom of chronic hepatitis C virus (cHCV) infection and a common side effect of interferon-based treatment for cHCV. This study provides confirmatory evidence of the reliability and validity of the Fatigue Severity Scale (FSS) to document fatigue in cHCV research and identifies values that indicate clinically important differences in FSS to aid in interpreting fatigue in cHCV clinical trials. METHODS: The study used data from two double-blind, randomized, placebo-controlled, Phase IIb trials evaluating the efficacy and safety of simeprevir plus peginterferon-α/ribavirin in treatment-naïve (PILLAR, n = 386) and treatment-experienced patients (ASPIRE, n = 462) with cHCV infection. Patients completed the FSS and EuroQoL 5 dimension questionnaire (EQ-5D) at baseline and at regular intervals throughout both trials. Reliability was assessed using Cronbach's coefficient α at Week 24 (internal consistency reliability) and intraclass correlation (ICC) between FSS at Weeks 12 and 24 in stable patients (<0.5 g/dL hemoglobin [Hb] change between Weeks 12/24). Correlation with the EQ-5D visual analog scale (VAS) and "Usual Activity" domain score was used to assess concurrent validity. Clinical validity was evaluated using a case-control method to link spontaneously reported fatigue and anemia adverse events (AEs) during the study to FSS scores. RESULTS: FSS total scores demonstrated good reliability (Cronbach's α: 0.95, 0.96; ICC: 0.74, 0.86 for PILLAR and ASPIRE, respectively) and concurrent validity (correlation with EQ-5D VAS: -0.63, -0.66) with a monotonic relationship between the EQ-5D "Usual Activities" item response and FSS. Clinical validity was confirmed by a significant difference between cases and controls for fatigue AEs (p < 0.05); however, anemia defined by AE or Hb abnormalities was only weakly related to FSS score. Analyses indicate that a change of 0.33-0.82 in mean FSS scores represents a meaningful improvement in fatigue, and a one-point change is a conservative indicator of an important change in individual FSS scores. CONCLUSION: A difference of ≥0.7 in mean FSS scores can be considered a clinically important difference within groups over time or between groups. A one-point change or less in individual FSS scores indicates a clinically relevant change in fatigue.

Once-daily simeprevir (TMC435) with pegylated interferon and ribavirin in treatment-naïve genotype 1 hepatitis C: the randomized PILLAR study.

UNLABELLED: The phase IIb, double-blind, placebo-controlled PILLAR trial investigated the efficacy and safety of two different simeprevir (SMV) doses administered once-daily (QD) with pegylated interferon (Peg-IFN)-α-2a and ribavirin (RBV) in treatment-naïve patients with HCV genotype 1 infection. Patients were randomized to one of five treatments: SMV (75 or 150 mg QD) for 12 or 24 weeks or placebo, plus Peg-IFN and RBV. Patients in the SMV arms stopped all treatment at week 24 if response-guided therapy (RGT) criteria were met; patients not meeting RGT continued with Peg-IFN and RBV until week 48, as did patients in the placebo control group. Sustained virologic response (SVR) rates measured 24 weeks after the planned end of treatment (SVR24) were 74.7%-86.1% in the SMV groups versus 64.9% in the control group (P < 0.05 for all comparisons [SMV versus placebo], except SMV 75 mg for 24 weeks). Rapid virologic response (HCV RNA <25 IU/mL undetectable at week 4) was achieved by 68.0%-75.6% of SMV-treated and 5.2% of placebo control patients. According to RGT criteria, 79.2%-86.1% of SMV-treated patients completed treatment by week 24; 85.2%-95.6% of these subsequently achieved SVR24. The adverse event profile was generally similar across the SMV and placebo control groups, with the exception of mild reversible hyperbilirubinemia, without serum aminotransferase abnormalities, associated with higher doses of SMV. CONCLUSION: SMV QD in combination with Peg-IFN and RBV significantly improves SVR rates, compared with Peg-IFN and RBV alone, and allows the majority of patients to shorten their therapy duration to 24 weeks.

Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.

PURPOSE: To determine the dose of trabectedin plus doxorubicin with granulocyte colony-stimulating factor support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLT) in patients with recurrent or persistent soft-tissue sarcoma. METHODS: In this phase I, open-label, multicenter trial, patients previously treated with 0-1 prior chemotherapy regimens excluding doxorubicin, an Eastern Cooperative Oncology Group performance status 0-1, and adequate organ function received a 10- to 15-min i.v. infusion of doxorubicin 60 mg/m(2) immediately followed by a 3-h i.v. infusion of trabectedin 0.9 to 1.3 mg/m(2) on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic granulocyte colony-stimulating factor. The maximum tolerated dose was the highest dose level with six or more patients in which less than one-third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events, tumor response, and survival were assessed. RESULTS: Patients (N = 41) received a median of six cycles of treatment (range, 2-13). The maximum tolerated dose was trabectedin 1.1 mg/m(2) and doxorubicin 60 mg/m(2). Common grade 3/4 treatment-emergent adverse events were neutropenia (71%), alanine aminotransferase increase (46%), and thrombocytopenia (37%). Overall, 5 (12%) patients achieved a partial response and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration. CONCLUSION: The combination of doxorubicin 60 mg/m(2) followed by trabectedin 1.1 mg/m(2) every 21 days is safe and active in patients with soft-tissue sarcoma.

Efficacy of montelukast for treating perennial allergic rhinitis.

Perennial allergic rhinitis (PAR) is a chronic inflammatory nasal condition in individuals exposed year-round to allergens. This was a double-blind study of 15- to 85-year-old patients randomly allocated to montelukast, 10 mg (n=630), placebo (n=613), or the positive control cetirizine, 10 mg (n=122) for 6 weeks. The primary efficacy end point was change from baseline in Daytime Nasal Symptoms Score (DNSS; mean of congestion, rhinorrhea, sneezing, and itching scores, rated daily by patients [scale: 0=none to 3=severe]) averaged during the initial 4 weeks (primary analysis) or entire 6 weeks of treatment. Also assessed were combined post hoc results of primary end point data from this study and another similarly designed study (Patel P, et al. Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis, Ann Allergy Asthma Immunol 95:551, 2005). Over 4 weeks, montelukast showed numerical improvement over placebo in DNSS (least-squares mean difference of -0.04 [95% confidence interval (CI}, -0.09, 0.01]); the difference between cetirizine and placebo was significant: -0.10 (95% CI, -0.19, -0.01). However, when averaged over 6 weeks, neither active treatment was significantly different from placebo. The Rhinoconjunctivitis Quality-of-Life score was significantly improved by montelukast (p < 0.05), but not by cetirizine, during 4 and 6 weeks. The treatment effect of montelukast, but not cetirizine, generally remained consistent through the 6 weeks of treatment. In pooled data, montelukast consistently improved DNSS versus placebo during all 6 weeks of treatment (-0.07 [95% CI, -0.10, -0.041). In conclusion, montelukast produced numerical improvement in daytime nasal symptoms and significant improvement in quality of life. In a pooled post hoc analysis, montelukast provided consistent improvement in daytime nasal symptoms over 6 weeks, supportive of an overall benefit in PAR.

Differential expression of hypoxia and (lymph)angiogenesis-related genes at different metastatic sites in breast cancer.

INTRODUCTION: Breast cancer can metastasize via lymphatic and hematogenous pathways. Hypoxia and (lymph)angiogenesis are closely related processes that play a pivotal role in the tumor progression and metastasis. The aim of this study was to compare expression of hypoxia and (lymph)angiogenesis-related genes between primary breast tumors and metastases in different tissues. MATERIALS AND METHODS: A gene list of 269 hypoxia and (lymph)angiogenesis-related genes was composed and validated using Onto-Express, Pathway-express and Ingenuity software. The expression of these genes was compared in microarray data of 62 samples of primary tumors and metastases of 31 patients with breast cancer retrieved from Gene Expression Omnibus. Similarity between samples was investigated using unsupervised hierarchical clustering analysis, principal component analysis and permutation testing. Differential gene expression between primary tumors and metastases and between metastases from different organs was analyzed using Kruskall-Wallis and Mann-Whitney statistics. RESULTS: Unsupervised hierarchical cluster analysis demonstrated that hypoxia and (lymph)angiogenesis-related gene expression was more similar between samples from the same patient, than between samples from the same organ. Principal component analysis indicated that 22.7% and 7.0% of the total variation in the gene list was respectively patient and organ related. When differences in gene expression were studied between different organs, liver metastases seemed to differ most from the other secondary sites. Some of the best characterized molecules differentially expressed were VEGFA, PDGFRB, FGF4, TIMP1, TGFB-R1 and collagen 18A1 (precursor of endostatin). To confirm the results of these experiments at the protein level, immunohistochemical experiments were performed with antibodies for VEGFA and MMP-2. CONCLUSIONS: Our results suggest that hypoxia and (lymph)angiogenesis-related gene expression is more dependent on the characteristics of the primary tumor than on the characteristics of the organs that bear the metastasis. However, when different organs are compared, the expression in liver metastases differs most from other metastatic sites and primary tumors, possibly due to organ-specific angiogenic and lymphangiogenic responses to metastasis-related hypoxia.

Montelukast, compared with fluticasone, for control of asthma among 6- to 14-year-old patients with mild asthma: the MOSAIC study.

BACKGROUND: Guidelines recommend daily controller therapy for mild persistent asthma. Montelukast has demonstrated consistent benefit in controlling symptoms of asthma and may be an alternative, orally administered, nonsteroidal agent for treating mild asthma. METHODS: The Montelukast Study of Asthma in Children (MOSAIC study) was a 12-month, multicenter, randomized, double-blind, noninferiority trial to determine the effect of once-daily, orally administered montelukast (5 mg) (n = 495), compared with twice-daily, inhaled fluticasone (100 microg) (n = 499), on the percentage of asthma rescue-free days (RFDs) (any day without asthma rescue medication and with no asthma-related resource use). Patients 6 to 14 years of age had mild persistent asthma (average percentage of predicted forced expiratory volume in 1 second: 87.2%; RFDs at baseline: 64%). Montelukast would be considered not inferior to fluticasone if the upper limit of the 95% confidence interval for the difference in mean percentages of RFDs (fluticasone minus montelukast) was above -7% (a difference of approximately 2 days/month). RESULTS: The mean percentage of RFDs was 84.0% in the montelukast group and 86.7% in the fluticasone group. The least-squares mean difference was -2.8% (95% confidence interval: -4.7% to -0.9%), within the noninferiority limit of -7%. The proportion of patients requiring systemic corticosteroids and the number of patients with an asthma attack were greater in the montelukast group. Both montelukast and fluticasone were well tolerated. CONCLUSIONS: Montelukast was demonstrated to be not inferior to fluticasone in increasing the percentage of RFDs among 6- to 14-year-old patients with mild asthma. Secondary end points, including percentage of predicted forced expiratory volume in 1 second value, days with beta-receptor agonist use, and quality of life, improved in both groups but were significantly better in the fluticasone treatment group.

Randomized, double-blind, placebo-controlled study of montelukast for treating perennial allergic rhinitis.

BACKGROUND: Perennial allergic rhinitis (PAR) is a persistent allergic inflammation of the upper respiratory tract due to year-round allergen exposure. OBJECTIVE: To evaluate the leukotriene receptor antagonist montelukast for the treatment of PAR. METHODS: Protocol 265 was a 2-arm study performed during the winter. After a placebo run-in period, adults with perennial allergen sensitivity and active symptoms of PAR were randomized to receive 10 mg of montelukast (n=1002) or placebo (n=990) once daily during a 6-week, double-blind, active-treatment period. The primary end point was the daytime nasal symptoms score, defined as the average of scores for nasal congestion, rhinorrhea, and sneezing rated daily by patients. RESULTS: Statistically significant improvements in PAR symptoms were seen in patients treated with montelukast. Their daytime nasal symptoms scores were reduced during treatment compared with those of the placebo group: the difference between treatments in least squares mean change from baseline was -0.08 (95% confidence interval [CI], -0.12 to -0.04; P < .001). Montelukast treatment also improved global evaluations of allergic rhinitis by patients and Rhinoconjunctivitis Quality of Life Questionnaire scores: differences vs the placebo group were -0.15 (95% CI, -0.27 to -0.04; P < .01) and -0.15 (95% CI, -0.24 to -0.06; P < .001), respectively. Other end points that showed statistically significant improvement with montelukast treatment were nighttime symptoms and each of the 4 nasal symptoms (congestion, rhinorrhea, sneezing, and itching). The treatment effects of montelukast were stable and persistent during the entire 6 weeks of treatment. CONCLUSION: Montelukast provided statistically significant relief of PAR symptoms during 6 weeks of treatment.

Montelukast reduces asthma exacerbations in 2- to 5-year-old children with intermittent asthma.

The PREVIA study was designed to investigate the role of montelukast, a leukotriene receptor antagonist, in the prevention of viral-induced asthma exacerbations in children aged 2 to 5 years with a history of intermittent asthma symptoms. The study was a 12-month multicenter, double-blind, parallel-group study of patients with asthma exacerbations associated with respiratory infections and minimal symptoms between episodes. Patients were randomized to receive oral montelukast 4 or 5 mg (depending on age) (n = 278) or placebo (n = 271) once per day for 12 months. Caregivers recorded children's symptoms, beta-agonist use, and health care resource use in a diary card. Over 12 months of therapy, montelukast significantly reduced the rate of asthma exacerbations by 31.9% compared with placebo. The average rate of exacerbation episodes per patient was 1.60 episodes per year on montelukast compared with 2.34 episodes on placebo. Montelukast also delayed the median time to first exacerbation by approximately 2 months (p = 0.024), and the rate of inhaled corticosteroid courses (p = 0.027) compared with placebo. Montelukast effectively reduced asthma exacerbations in 2- to 5-year-old patients with intermittent asthma over 12 months of treatment and was generally well tolerated.

Different effects of antihypertensive therapies based on losartan or atenolol on ultrasound and biochemical markers of myocardial fibrosis: results of a randomized trial.

BACKGROUND: In hypertensive left ventricular hypertrophy (LVH), myocardial texture is altered by a disproportionate increase in fibrosis, but there is insufficient clinical evidence whether antihypertensive therapy or individual agents can induce regression of myocardial fibrosis. METHODS AND RESULTS: We compared the effects of an angiotensin II receptor antagonist with a beta-blocker on myocardial collagen volume (assessed by echoreflectivity and serum collagen markers) in 219 hypertensive patients with echocardiographically documented LVH. Patients were allocated randomly to receive losartan 50 to 100 mg/d (n=111) or atenolol 50 to 100 mg/d (n=99) with or without hydrochlorothiazide 12.5 to 25 mg/d for 36 weeks. Echoreflectivity analysis was conducted on ultrasound tracings of the midapex septum with specifically designed and validated software. A color histogram of reflecting echoes was obtained, and its spread (broadband [BB], previously shown to correlate directly with collagen volume fraction on endomyocardial biopsies) was used as the primary outcome measure. Mean color scale and serum markers of collagen synthesis (PIP, PIIIP) or degradation (CITP) were secondary outcome variables. Echoreflectivity analysis proved feasible in 106 patients (losartan 52, atenolol 54). Losartan reduced BB over 36 weeks (from 114.5 to 104.3 color levels, P<0.02), whereas atenolol treatment was associated with an increase in BB (from 109.0 to 113.6 color levels, P=NS), the difference between treatments being -12.8 color levels (95% CI -23.6 to -2.0, P=0.02). Secondary end points (mean color scale and collagen markers) also changed in the direction of decreased collagen in patients receiving losartan, but differences between groups were not statistically significant. CONCLUSIONS: In hypertensive patients with LVH, losartan decreases myocardial collagen content, whereas atenolol does not. The difference between the 2 treatments is statistically significant.

Comparison of the blood pressure-lowering effects and tolerability of Losartan- and Amlodipine-based regimens in patients with isolated systolic hypertension.

BACKGROUND: Elevated systolic blood pressure is a more important risk factor for cardiovascular and renal disease than elevated diastolic blood pressure. Isolated systolic hypertension (ISH) is the predominant form of hypertension in the elderly. Effects of angiotensin II on the vascular wall and endothelium may contribute to development of ISH. OBJECTIVE: The primary objective of this study was to compare the effects on trough sitting systolic blood pressure (SiSBP) of a regimen of losartan, a selective angiotensin II-receptor antagonist, and an amlodipine-based regimen in patients with ISH. METHODS: This multicenter, prospective, randomized, double-blind, parallel-group study consisted of a 4-week placebo phase and an 18-week active-treatment phase. The losartan-based regimen consisted of losartan 50 mg, increased as needed to losartan 50 mg/hydrochlorothiazide (HCTZ) 12.5 mg at week 6 and to losartan 100 mg/HCTZ 25 mg at week 12 to achieve a target SiSBP <140 mm Hg. the amlodipine-based regimen consisted of amlodipine 5 mg, increased as needed to amlodipine 10 mg at week 6 and to amlodipine 10 mg/HCTZ 25 mg at week 12. The primary efficacy measure was change in trough SiSBP from baseline to week 18. Information on the tolerability of study treatments was collected at each visit, including the investigator's and patient's observations of clinical adverse experiences (CAEs), laboratory adverse experiences, and responses to a symptom questionnaire. RESULTS: Eight hundred fifty-seven patients (65.6% female) were randomized to treatment, 432 in the losartan group and 425 in the amlodipine group. Their mean age was 67.6 years, and they had a mean duration of hypertension of 6.7 years at baseline. The losartan and amlodipine groups (intent-to-treat population) had baseline mean SiSBP values of 171.2 and 171.9 mm Hg, respectively. At week 18 (the primary end point), the mean change from baseline in SiSBP was -27.4 mm Hg for 426 patients who received losartan and -28.1 mm Hg for 419 patients who received amlodipine (estimated least-square mean difference, 0.3 mm Hg; 95% CI, -1.4 to 2.0), indicating that losartan's effect on systolic blood pressure was noninferior to that of amlodipine. The proportion of patients who responded (SiSBP <140 mm Hg or a > or =20-mm Hg decrease in SiSBP from baseline) was comparable between groups (73.9% losartan, 75.4% amlodipine). The incidence of CAEs and drug-related CAEs was significantly greater in the amlodipine group (amlodipine, 79.8% and 43.8%, respectively; losartan, 67.8% and 25.5%; P < or = 0.001). In addition, more patients in the amlodipine group discontinued therapy due to a drug-related CAE compared with patients in the losartan group (12.9% vs 4.4%, respectively; P < or = 0.001). Lower-extremity edema was the most common drug-related CAE in the amlodipine group (24.0% amlodipine, 2.5% losartan; P < or = 0.001); dizziness was the most common drug-related CAE in the losartan group (6.0% losartan, 4.0% amlodipine). CONCLUSIONS: In these patients with ISH, losartan and amlodipine produced comparable clinically relevant reductions in SiSBP; however, losartan was better tolerated, as evidenced by fewer CAEs and discontinuations compared with amlodipine. Losartan may be considered for the initial treatment of ISH.