Joint longitudinal model-based meta-analysis of FEV1 and exacerbation rate in randomized COPD trials

Model-based meta-analysis (MBMA) is an approach that integrates relevant summary level data from heterogeneously designed randomized controlled trials (RCTs). This study not only evaluated the predictability of a published MBMA for forced expiratory volume in one second (FEV1) and its link to annual exacerbation rate in patients with chronic obstructive pulmonary disease (COPD) but also included data from new RCTs. A comparative effectiveness analysis across all drugs was also performed. Aggregated level data were collected from RCTs published between July 2013 and November 2020 (n = 132 references comprising 156 studies) and combined with data used in the legacy MBMA (published RCTs up to July 2013 - n = 142). The augmented data (n = 298) were used to evaluate the predictive performance of the published MBMA using goodness-of-fit plots for assessment. Furthermore, the model was extended including drugs that were not available before July 2013, estimating a new set of parameters. The legacy MBMA model predicted the post-2013 FEV1 data well, and new estimated parameters were similar to those of drugs in the same class. However, the exacerbation model overpredicted the post-2013 mean annual exacerbation rate data. Inclusion of year when the study started on the pre-treatment placebo rate improved the model predictive performance perhaps explaining potential improvements in the disease management over time. The addition of new data to the legacy COPD MBMA enabled a more robust model with increased predictability performance for both endpoints FEV1 and mean annual exacerbation rate

Improved Confidence in a Confirmatory Stage by Application of Item-Based Pharmacometrics Model : Illustration with a Phase III Active Comparator-Controlled Trial in COPD Patients

Purpose The current study aimed to illustrate how a non-linear mixed effect (NLME) model-based analysis may improve confidence in a Phase III trial through more precise estimates of the drug effect. Methods The FULFIL clinical trial was a Phase III study that compared 24 weeks of once daily inhaled triple therapy with twice daily inhaled dual therapy in patients with chronic obstructive pulmonary disease (COPD). Patient reported outcome data, obtained by using The Evaluating Respiratory Symptoms in COPD (E-RS:COPD) questionnaire, from the FULFIL study were analyzed using an NLME item-based response theory model (IRT). The change from baseline (CFB) in E-RS:COPD total score over 4-week intervals for each treatment arm was obtained using the IRT and compared with published results obtained with a mixed model repeated measures (MMRM) analysis. Results The IRT included a graded response model characterizing item parameters and a Weibull function combined with an offset function to describe the COPD symptoms-time course in patients receiving either triple therapy (n = 907) or dual therapy (n = 894). The IRT improved precision of the estimated drug effect compared to MMRM, resulting in a sample size of at least 3.64 times larger for the MMRM analysis to achieve the IRT precision in the CFB estimate. Conclusion This study shows the advantage of IRT over MMRM with a direct comparison of the same primary endpoint for the two analyses using the same observed clinical trial data, resulting in an increased confidence in Phase III

Pharmacokinetics of the nitric oxide synthase inhibitor L-N(G)- methylarginine hydrochloride in patients with septic shock

Objectives: To characterize the pharmacokinetics of L-N(G)- methylarginine in patients with septic shock. Methods: This was an international, uncontrolled, open-label study of L-N(G)-methylarginine (546C88) therapy given to 32 patients with septic shock. It was conducted in hospital-based intensive care units that admit general surgical and medical patients. Patient cohorts received an infusion of L-N(G)-methylarginine at fixed dose rates of 1, 2.5, 5, 10, and 20 mg/kg/h for up to 8 hours. The 5 dosing regimens were administered sequentially to separate groups of patients. Results: Of the 32 patients studied, 23 received complete 8-hour infusions. In the other 9 patients, the infusion was terminated prematurely within the first 1/2 to 4 hours. Median clearance of L-N(G)-methylarginine averaged 485 mL/h/kg for the 1 and 2.5 mg/kg/h dosing cohorts combined but decreased to 283, 181, and 98 mL/h/kg for the 5, 10, and 20 mg/kg/h dosing cohorts, respectively. Median renal clearance was similar at 9 to 26 mL/h for the 1, 2.5, and 5 mg/kg/h dosing cohorts but increased to 156 and 284 mL/h for the 10 and 20 mg/kg/h dosing cohorts, respectively. Median steady-state volume of distribution was similar in all 5 dosing cohorts, averaging 0.66 to 0.82 L/kg. Conclusions: The 80% decrease in clearance from 485 to 98 mL/h/kg with the increase in dose suggests that a predominant metabolic pathway(s) of L-N(G)-methylarginine, accounting for at least 80% of clearance, is becoming progressively saturable in association with L-N(G)-methylarginine infusion rates ≥5 mg/kg/h. Therefore the use of L-N(G)-methylarginine infusion rates ≥5 mg/kg/h are typically expected to result in progressive inhibition of nitric oxide synthase activity. Consequently, patient hemodynamics should be monitored closely to avoid an excessive increase in vasomotor tone, which would be manifest by either an increase in mean arterial pressure or a decrease in cardiac output. The infusion rates of conventional vasopressor(s) (eg, norepinephrine [BAN, noradrenaline]) or L-N(G)-methylarginine or both may need to be reduced accordingly.SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Inhibition of capsaicin-driven nasal hyper-reactivity by SB-705498, a TRPV1 antagonist

To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB-705498, a selective TRPV1 antagonist. Two randomized, double-blind, placebo-controlled, clinical studies were performed: (i) an intranasal SB-705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non-allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB-705498 against nasal capsaicin challenge. Single and repeat dosing with intranasal SB-705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB-705498 and placebo and no dose-dependent increase was observed. Administration of SB-705498 resulted in less than dose proportional AUC(0,12 h) and Cmax , while repeat dosing from day 1 to day 14 led to its accumulation. SB-705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB-705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2- to 4-fold shift in capsaicin potency. Intranasal SB-705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin-provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB-705498 may have in rhinitis treatment deserves further evaluatio

Adaptive study design to assess effect of TRPV4 inhibition in patients with chronic cough

Objective Airway sensory nerves involved in the cough reflex are activated by adenosine triphosphate (ATP) agonism of P2X purinoceptor 3 (P2X3) receptors. Transient receptor potential vanilloid 4 (TRPV4) channel activation causes ATP release from airway cells, and it is hypothesised that a TRPV4-ATP-P2X3 axis contributes to chronic cough. An adaptive study was run to determine if TRPV4 inhibition, using the selective TRPV4 channel blocker GSK2798745, was effective in reducing cough. Methods A two-period randomised, double blinded, placebo-controlled crossover study was designed with interim analyses for futility and sample size adjustment. Refractory chronic cough patients received either GSK2798745 or placebo once daily for 7 days with a washout between treatments. Pharmacokinetic samples were collected for analysis of GSK2798745 at end of study. The primary end-point was total cough counts assessed objectively during day-time hours (10 h) following 7 days of dosing. Results Interim analysis was performed after 12 participants completed both treatment periods. This showed a 32% increase in cough counts on Day 7 for GSK2798745 compared to placebo; the pre-defined negative criteria for the study were met and the study was stopped. At this point 17 participants had been enrolled (mean 61 years; 88% female), and 15 had completed the study. Final study results for posterior median cough counts showed a 34% (90% credible interval: −3%, +85%) numerical increase for GSK2798745 compared to placebo. Conclusion There was no evidence of an anti-tussive effect of GSK2798745. The study design allowed the decision on lack of efficacy to be made with minimal participant exposure to the investigational drug

An open label trial of nemiralisib, an inhaled PI3 kinase delta inhibitor for the treatment of Activated PI3 kinase Delta Syndrome.

Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS

Selective androgen receptor modulation for muscle weakness in chronic obstructive pulmonary disease: a randomised control trial

BackgroundSelective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength in patients with chronic obstructive pulmonary disease (COPD) and impaired physical function.Methods47 postmenopausal women and 50 men with COPD (forced expiratory volume in 1 s 30%-65% predicted; short physical performance battery score: 3-11) were enrolled into a randomised double-blind, placebo control trial. Patients were randomised 1:1 to once daily placebo or oral GSK2881078 (females: 1.0 mg; males: 2.0 mg) for 13 weeks with a concurrent home-exercise programme, involving strength training and physical activity. Primary endpoints were change from baseline in leg strength at 90 days (one-repetition maximum; absolute (kg) and relative (% change)) and multiple safety outcomes. Secondary endpoints included lean body mass, physical function and patient-reported outcomes.ResultsGSK2881078 increased leg strength in men. The difference in adjusted mean change from baseline and adjusted mean percentage change from baseline between treatment and placebo were: for women, 8.0 kg (90% CI -2.5 to 18.4) and 5.2% (90% CI -4.7 to 15.0), respectively; for men, 11.8 kg (90% CI -0.5 to 24.0) and 7.0% (90% CI 0.5 to 13.6), respectively. Lean body mass increased, but no changes in patient-reported outcomes were observed. Reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings.ConclusionsGSK2881078 was well tolerated and short-term treatment increased leg strength, when expressed as per cent predicted, in men with COPD more than physical training alone.Trial registration numberNCT03359473