Paul Stryszak

Safety and efficacy of a CXCR2 antagonist in patients with severe asthma and sputum neutrophils: a randomized, placebo-controlled clinical trial.

Increased numbers of neutrophils are reported in the airways of patients with severe asthma. It is not clear if they contribute to the lack of control and severity. There are currently no strategies to investigate this by decreasing neutrophil numbers in the airways.

CXCR2 Antagonist MK-7123. A Phase 2 Proof-of-Concept Trial for Chronic Obstructive Pulmonary Disease

RATIONALEnAn antagonist (MK-7123) of the cytokine receptor CXCR2 reduces neutrophil chemotaxis and thus may alleviate airway inflammation in chronic obstructive pulmonary disease (COPD).nnnOBJECTIVESnTo assess the efficacy, safety, and tolerability of three dose levels of MK-7123, compared with placebo, in patients with moderate to severe COPD.nnnMETHODSnThis 6-month, double-blind study randomized patients with moderate to severe COPD (already on standard therapy) to daily MK-7123 at 10, 30, or 50 mg or placebo. The primary endpoint was change from baseline in post-bronchodilator FEV1.nnnMEASUREMENTS AND MAIN RESULTSnA total of 616 patients (71% male; mean age, 63 yr; 45% current smokers; baseline FEV1 [SD], 1.43 L [0.45]; mean FEV1 percent predicted, 43.9%) were randomized. Only MK-7123 50 mg led to significant improvement in FEV1 over placebo (mean difference [SE], 67 ml [32]). Reduced sputum neutrophil count was observed among the 122 patients examined; Pu2009=u20090.003 (3 mo) and Pu2009=u20090.092 (6 mo) (MK-7123 50 mg vs. placebo). The stratum of current smokers, but not that of nonsmokers, showed significant improvement versus placebo in FEV1 (168 ml) and time-to-first exacerbation, and showed numerical improvement in St. Georges Respiratory Questionnaire for COPD score. MK-7123 caused a dose-dependent decrease in absolute neutrophil count (ANC) and reduced inflammatory biomarkers matrix metallopeptidase-9 and myeloperoxidase in plasma and sputum; ANC lower than 1.5u2009×u200910(9)/L led to discontinuations with higher doses of MK-7123 (18% in the MK-7123 50-mg group vs. 1% in placebo). Plasma C-reactive protein and fibrinogen increased with MK-7123 treatment. Rates of infections at 6 months were similar in all groups.nnnCONCLUSIONSnTreatment with MK-7123 50 mg versus placebo led to significant improvement in FEV1 in patients with COPD, suggesting clinically important antiinflammatory effects with CXCR2 antagonism, although dose-related discontinuations were observed because of ANC decreases with MK-7123. Greater response was observed in smokers versus ex-smokers. Clinical trial registered with www.clinicaltrials.gov (NCT 01006616).

Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection

BACKGROUND & AIMSnPatients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population.nnnMETHODSnWe analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%).nnnRESULTSnWith 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferonxa0and ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%).nnnCONCLUSIONSnThe combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

Effects of Inhaled Mometasone Furoate on Growth Velocity and Adrenal Function: A Placebo-Controlled Trial in Children 4–9 Years Old with Mild Persistent Asthma

Objective. To assess the effects of long-term mometasone furoate delivered via a dry powder inhaler (MF-DPI) on growth velocity and hypothalamic–pituitary–adrenal axis function in children with asthma. Study design. Children aged 4–9 years with asthma (n = 187) were randomized to MF-DPI 100 μg (delivered dose; actuated dose is 110 μg) once daily in the morning (QD AM), 100 μg twice daily (BID), 200 μg QD AM, or placebo for 52 weeks followed by a 3-month follow-up period. The primary outcome was growth velocity calculated from stadiometric heights recorded at each visit. Secondary outcomes included serum and 12-h urinary cortisol, serum osteocalcin, and urinary N-telopeptide. Results. MF-DPI 100 μg QD AM treatment did not significantly affect growth velocity compared with placebo (–0.10 ± 0.31 cm/y, p = 0.76). When the effect of a total daily dose of 200 μg MF-DPI on growth velocity was examined, no significant effect was demonstrated for MF-DPI 100 μg BID compared with placebo (–0.64 ± 0.39 cm/y, p = 0.10), although the change in mean growth velocity with MF-DPI 200 μg QD AM reached statistical significance (–0.70 ± 0.29 cm/y, p = 0.02). The effects of all examined doses of MF-DPI on mean plasma cortisol levels were similar to cortisol changes seen in the placebo group, suggesting an absence of drug-related effects. No differences in 12-h urinary cortisol or other outcomes were observed between groups. Conclusions. One year of treatment with a total daily dose of 100 μg of MF-DPI in the morning resulted in no significant difference, whereas a total daily dose of 200 μg of MF-DPI was associated with some changes in growth velocity when compared with placebo. The differences in growth velocity, and the absence of drug-related cortisol effects, support the use of a total daily dose of 100 μg of MF-DPI in children aged 4–9 years with mild persistent asthma.

Safety of mometasone furoate nasal spray in the treatment of nasal polyps in children.

Mometasone furoate nasal spray (MFNS) improves nasal symptoms and reduces polyp size in adults with nasal polyposis. This 4‐month, multinational, randomized, double‐blind study was conducted to assess the safety of MFNS in pediatric subjects aged 6–17 yr.

Humoral immunity and delayed-type hypersensitivity in healthy subjects treated for 30 days with MK-7123, a selective CXCR2 antagonist

Antagonism of the chemokine receptor CXCR2 inhibits neutrophil trafficking and may thus be therapeutic in patients with chronic obstructive pulmonary disease and other lung disorders in which there is substantial infiltration by neutrophils. Here, we report the findings from a randomized, placebo-controlled, double-blind clinical trial of the small-molecule CXCR2 antagonist MK-7123 (formerly SCH 527123) that evaluated potential downstream effects of CXCR2 antagonism on immunogenic competency (B cell antibody response) in the adaptive immune system and delayed-type hypersensitivity (DTH) in healthy subjects (ages 34-65 years) dosed once daily for 30 days either with 30 mg MK-7123 (n=24) or placebo (n=7). Eligible subjects were seronegative for anti-hepatitis A virus (HAV) immunoglobulin G (IgG) and positive for DTH response to intradermal injection of Candida albicans antigen at screening. Subjects were vaccinated for HAV on treatment Day 2. The primary endpoints were anti-HAV IgG titer on Day 30 and DTH response magnitude on Day 27. Pharmacokinetic and safety endpoints were also assessed. We observed that anti-HAV IgG titers and DTH responses did not differ significantly between MK-7123-treated and placebo-treated subjects. Twenty-eight days postvaccination, seroconversion (anti-HAV IgG titer≥10mIU/mL) was observed in 87.5% and 85.7% of MK-7123-treated and placebo-treated subjects, respectively; mean (±SE) titers were 27.3±5.5 and 21.4±4.3mIU/mL, respectively. Treatment with MK-7123 was generally well tolerated. Doses were followed by temporary reductions in absolute peripheral blood neutrophil count. In conclusion, this study found that B cell response and cell-mediated immunity were not altered by CXCR2 antagonism with MK-7123.

Evaluation of two doses of etoricoxib, a COX-2 selective non-steroidal anti-inflammatory drug (NSAID), in the treatment of Rheumatoid Arthritis in a double-blind, randomized controlled trial

BackgroundTreatment with non-steroidal anti-inflammatory drugs (NSAID) is a common component of treatment regimens for rheumatoid arthritis (RA). Etoricoxib is a COX-2 selective NSAID that has demonstrated efficacy in the treatment of RA at a dose of 90 mg. The current study further evaluated the efficacy of etoricoxib 60 mg and 90 mg in RA patients with active disease.MethodsThis was a 2-part, double-blind, placebo-controlled study in RA (NCT01208181). Patients were required to have a diagnosis of RA (according to ARA 1987 revised classification criteria) and were to demonstrate symptom flare upon discontinuation of previous NSAID treatment prior to randomization. Part I was a 6-week, placebo-controlled period to assess the efficacy of etoricoxib 90 mg and etoricoxib 60 mg, each compared to placebo, as well as to each other. Part II was a 6-week period to evaluate the potential benefit of dose escalation from etoricoxib 60 mg to etoricoxib 90 mg after 6 weeks exposure to etoricoxib 60 mg in Part I compared to maintaining a steady dose of etoricoxib 60 mg throughout Parts I and II. Primary endpoints were Disease Activity Score evaluating 28 joints and C reactive protein level (DAS28-CRP) index and Patient Global Assessment of Pain (Pain) score (0–100 mm VAS) after 6 weeks of treatment in Part I. Adverse events were monitored throughout the study.ResultsIn total, 1404 patients were randomized in a 2:7:7:8 ratio; 1228 patients completed Part I and 713 patients continued to Part II. Both etoricoxib doses were superior to placebo on both primary efficacy endpoints (pu2009=u20090.004 for 60 mg and pu2009=u20090.034 for 90 mg for DAS28-CRP; pu2009<u20090.001 for both doses for PGAP) in Part I. Further in Part I, etoricoxib 90 mg was not significantly different from 60 mg for DAS28-CRP, but did demonstrate a small, but statistically significant decrease in baseline PGAP score vs. 60 mg (pu2009=u20090.019). In Part II, there was no significant decrease in PGAP score after increasing to 90 mg in subjects with inadequate pain relief on 60 mg as compared to subjects who stayed on 60 mg. The incidence of AEs and SAEs were similar between etoricoxib 60 mg and 90 mg in both Part I and II.ConclusionBoth etoricoxib 90 mg and 60 mg are superior to placebo in relieving the symptoms of RA. Etoricoxib 90 mg vs 60 mg resulted in a statistically significant, though small, improvement in PGAP score, but not DAS28-CRP. Dose escalation from 60 mg to 90 mg in pain inadequate responders did not significantly improve efficacy. These results confirm the efficacy and tolerability of etoricoxib 90mg in patients with RA. In addition, this study demonstrated that etoricoxib 60 mg is also efficacious and well-tolerated in RA.Clinical Trial RegistrationNCT01208181 (registered September 22, 2010).

A randomized, clinical trial to assess the relative efficacy and tolerability of two doses of etoricoxib versus naproxen in patients with ankylosing spondylitis.

BackgroundThis study evaluated two doses of etoricoxib (60 and 90xa0mg) vs. naproxen 1000xa0mg in subjects with ankylosing spondylitis (AS).MethodsThis was a 2-part, double-blind, active comparator-controlled non-inferiority study in subjects ≥18xa0years of age with AS. In Part I, subjects were randomized to naproxen 1000xa0mg; etoricoxib 60xa0mg, and 90xa0mg. In Part II, naproxen and etoricoxib 90xa0mg subjects continued on the same treatment; subjects on etoricoxib 60xa0mg either continued on 60xa0mg or escalated to 90xa0mg. Part I (6xa0weeks) assessed the efficacy of A) etoricoxib 60xa0mg vs. naproxen and B) 90xa0mg vs. naproxen according to the time-weighted average change from baseline in Spinal Pain Intensity (SPI; 0–100xa0mm VAS) (primary endpoint). The non-inferiority margin was set at 8xa0mm for SPI. In Part II (20xa0weeks) we evaluated the potential benefit of increasing from 60 to 90xa0mg (predefined minimum clinically important differenceu2009=u20096xa0mm in SPI) for inadequate responders (<50xa0% improvement from baseline in SPI) on etoricoxib 60xa0mg in Part I.ResultsIn total, 1015 subjects were randomized to receive etoricoxib 60xa0mg (Nu2009=u2009702), etoricoxib 90xa0mg (Nu2009=u2009156), and naproxen 1000xa0mg (Nu2009=u2009157); 70.9xa0% were male and the mean age was 45.2xa0years. There were 919 subjects who completed Part I and all continued to Part II. In Part I, SPI change was non-inferior for both etoricoxib doses vs. naproxen. In both Part I and II, the incidence of adverse events (AEs), drug-related AEs, and serious adverse events (SAEs) were similar between the 3 treatment groups.ConclusionBoth doses of etoricoxib were non-inferior to naproxen. All treatments were well tolerated. Etoricoxib 60 and 90xa0mg effectively control pain in patients with AS, with 60xa0mg once daily as the lowest effective dose for most patients.Trial registrationClinical Trials Registry # NCT01208207. Registered on 22 September 2010.