A model-based approach for historical borrowing, with an application to neovascular age-related macular degeneration.

Bayesian historical borrowing has recently attracted growing interest due to the increasing availability of historical control data, as well as improved computational methodology and software. In this article, we argue that the statistical models used for borrowing may be suboptimal when they do not adjust for differing factors across historical studies such as covariates, dosing regimen, etc. We propose an alternative approach to address these shortcomings. We start by constructing a historical model based on subject-level historical data to accurately characterize the control treatment by adjusting for known between trials differences. This model is subsequently used to predict the control arm response in the current trial, enabling the derivation of a model-informed prior for the treatment effect parameter of another (potentially simpler) model used to analyze the trial efficacy (i.e. the trial model). Our approach is applied to neovascular age-related macular degeneration trials, employing a cross-sectional regression trial model, and a longitudinal non-linear mixed-effects drug-disease-trial historical model. The latter model characterizes the relationship between clinical response, drug exposure and baseline covariates so that the derived model-informed prior seamlessly adapts to the trial population and can be extrapolated to a different dosing regimen. This approach can yield a more accurate prior for borrowing, thus optimizing gains in efficiency (e.g. increasing power or reducing the sample size) in future trials.

Pharmacokinetic and Pharmacodynamic Comparison of Fluticasone Propionate/Formoterol Fumarate Administered via a Pressurized Metered-Dose Inhaler and a Novel Breath-Actuated Inhaler in Healthy Volunteers.

Introduction: Fluticasone propionate/formoterol fumarate (fluticasone/formoterol) exposures, following administration of Flutiform® K-haler®, a breath-actuated inhaler (BAI), were compared with the Flutiform pressurized metered-dose inhaler (pMDI) with/without spacer in two healthy volunteer studies. In addition, formoterol-induced systemic pharmacodynamic (PD) effects were examined in the second study. Methods: Study 1: single-dose, three-period, crossover pharmacokinetic (PK) study with oral charcoal administration. Fluticasone/formoterol 250/10 µg was administered via BAI, pMDI, or pMDI with spacer (pMDI+S). Pulmonary exposure for BAI was deemed no less than for pMDI (primary comparator) if the lower limit of 94.12% confidence intervals (CIs) for BAI:pMDI maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUCt) ratios was ≥80%. Study 2: two-stage adaptive design, both stages being single-dose, crossover without charcoal administration. The PK stage compared fluticasone/formoterol 250/10 µg via BAI, pMDI, or pMDI+S. The primary comparisons were as follows: BAI versus pMDI+S for fluticasone and BAI versus pMDI for formoterol. Systemic safety with BAI was deemed no worse than primary comparator if the upper limit of 94.12% CIs for Cmax and AUCt ratios was ≤125%. PD assessment was to be conducted if BAI safety was not confirmed in the PK stage. Based on PK results, only formoterol PD effects were evaluated. The PD stage compared fluticasone/formoterol 1500/60 µg via BAI, pMDI, or pMDI+S; fluticasone/formoterol 500/20 µg pMDI; and formoterol 60 µg pMDI. The primary endpoint was maximum reduction in serum potassium within 4 hours postdose. Equivalence was defined as 95% CIs for BAI versus pMDI+S and pMDI ratios within 0.5-2.0. Results: Study 1: lower limit of 94.12% CIs for BAI:pMDI ratios >80%. Study 2, PK stage: upper limit of 94.12% CIs for fluticasone (BAI:pMDI+S) ratios <125%; upper limit of 94.12% CIs for formoterol (BAI:pMDI) ratios >125% (for Cmax, not AUCt). Study 2, PD stage: 95% CIs for serum potassium ratios 0.7-1.3 (BAI:pMDI+S) and 0.4-1.5 (BAI:pMDI). Conclusions: Fluticasone/formoterol BAI performance was within the range observed for the pMDI with/without a spacer. Sponsor: Mundipharma Research Ltd. EudraCT 2012-003728-19 (Study 1) and 2013-000045-39 (Study 2).

Paediatric reference range for overnight urinary cortisol corrected for creatinine.

OBJECTIVES: Systemic activity of inhaled corticosteroids (ICS) may be assessed via urinary cortisol measurement. Overnight urinary free cortisol corrected for creatinine (OUFCC) has been extensively reported in adult studies. However, a paediatric mass spectrometric (MS) reference range for OUFCC is not established. MS methods for OUFCC avoid cross-reactivity with other steroid hormones and are thus preferable to immunoassays. The aim of the present study was to define an MS OUFCC normative range in children. METHODS: This was a cross-sectional study of healthy pre-pubertal children from 5 to 11 years. Children collected urine from 10 pm or bedtime, whichever was earlier, until 8 am. Urinary free cortisol was measured via a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay (Acquity UPLC with Xevo TQ-S Mass Spectrometer [Waters]) with in-house reagents. Urinary creatinine was measured using a commercial assay (Roche). RESULTS: Complete urine collections were obtained from 72 males and 70 females, mean age (SD) 8.6 (1.9) (range 5.0-11.8) years. The OUFCC 95% prediction interval was 1.7-19.8 nmol/mmol. Geometric mean OUFCC was 5.7; range 1.1-24.8 nmol/mmol. CONCLUSIONS: The obtained normative LC-MS/MS OUFCC reference data facilitate the use of mass spectrometry OUFCC assays in assessment of systemic activity of endogenous and exogenous corticosteroids in children.

Low-dose methoxyflurane analgesia in adolescent patients with moderate-to-severe trauma pain: a subgroup analysis of the STOP! study.

INTRODUCTION: The undertreatment of acute pain presents a significant challenge in the Emergency Department. This post hoc subgroup analysis of a previously reported randomized controlled UK study reports the efficacy and safety of low-dose methoxyflurane analgesia in treating adolescent patients with moderate-to-severe trauma pain. PATIENTS AND METHODS: Three hundred patients (96 in the adolescent subgroup) aged ≥12 years requiring analgesia for acute trauma pain (pain score of 4-7 on the Numerical Rating Scale) at triage were randomized 1:1 to methoxyflurane (up to 6 mL) or placebo (normal saline), both administered using a Penthrox® inhaler. The patient could request rescue medication (paracetamol/opioids) at any time. The primary endpoint was the change from baseline in visual analog scale (VAS) pain intensity. RESULTS: Mean VAS pain score for the adolescent subgroup at baseline was ~ 61 mm. Adjusted mean change in VAS pain intensity from baseline to 5, 10, 15, and 20 minutes was -24.5, -28.1, -31.6, and -31.7 mm for methoxyflurane and -14.6, -18.8, -19.2, and -23.7 mm for placebo, with a statistically significant treatment effect in favor of methoxyflurane overall across all four time points (-9.9 mm; 95% CI: -17.4, -2.4 mm; P=0.0104). Median time to first pain relief was significantly shorter with methoxyflurane (1 minute) than placebo (3 minutes, P<0.0001). Pain relief was reported within 1-10 inhalations in 95.7% of methoxyflurane-treated patients and 64.6% of placebo-treated patients. Rescue medication was requested by two (4.3%) methoxyflurane-treated patients and three (6.3%) placebo-treated patients. Over 95% of patients, physicians, and nurses rated methoxyflurane treatment as "Excellent", "Very Good" or "Good" compared with between 64% and 68% for placebo. The incidence of adverse events was higher with methoxyflurane (51%) than placebo (42%), mostly comprising mild/transient dizziness and headache. CONCLUSION: This subgroup analysis shows that low-dose inhaled methoxyflurane is a rapid-acting and effective analgesic in adolescent patients presenting with moderate-to-severe trauma pain. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

Pulmonary deposition of fluticasone propionate/formoterol in healthy volunteers, asthmatics and COPD patients with a novel breath-triggered inhaler.

INTRODUCTION: A combination of fluticasone propionate/formoterol fumarate (FP/FORM) has been incorporated within a novel, breath-triggered device, named K-haler®. This low resistance device requires a gentle inspiratory effort to actuate it, triggering at an inspiratory flow rate of approximately 30 L/min; thus avoiding the need for coordination of inhalation with manual canister depression. The aim of the study was to evaluate total and regional pulmonary deposition of FP/FORM when administered via the K-haler device. MATERIALS AND METHODS: Twelve healthy subjects, 12 asthmatics, and 12 COPD patients each received a single dose of 2 puffs 99mtechnetium-labelled FP/FORM 125/5 µg. A gamma camera was used to obtain anterior and posterior two-dimensional images of drug deposition. Prior transmission scans (using a99mtechnetium flood source) allowed the definition of regions of interest and calculation of attenuation correction factors. Image analysis was performed per standardised methods. RESULTS: Of 36 subjects, 35 provided evaluable post-dose scintigraphic data. Mean subject ages were 35.7 (healthy), 44.5 (asthma) and 61.7 years (COPD); mean FEV1% predicted values were 109.8%, 77.4% and 43.2%, respectively. Mean pulmonary deposition was 26.6% (healthy), 44.7% (asthma), 39.0% (COPD) of the delivered dose. The respective mean penetration indices (peripheral:central ratio normalised to a transmission lung scan) were 0.44, 0.31 and 0.30. CONCLUSION: FP/FORM administration via the K-haler device resulted in high lung deposition in patients with obstructive lung disease but somewhat lesser deposition in healthy subjects. Regional deposition data demonstrated drug deposition in both the central and peripheral regions in all subject populations. EUDRACT NUMBER: 2015-000744-42.

A Randomized, Crossover Trial Evaluating Patient Handling, Preference, and Ease of Use of the Fluticasone Propionate/Formoterol Breath-Triggered Inhaler.

BACKGROUND: Appropriate inhaler selection is of fundamental importance in obstructive lung disease management. Key factors in device selection include a patient's capacity to operate a particular device and their preference for it. METHODS: This randomized, open-label, two-period, crossover study (NCT01739387) compared the ability of adolescent and adult patients with obstructive lung disease to correctly handle the fluticasone propionate/formoterol fumarate (FP/FORM; Flutiform®) pressurized metered-dose inhaler (pMDI) and FP/FORM K-haler®, a novel breath-triggered inhaler (BTI), following a simple, standardized training regimen. The primary endpoint was the ability to perform all steps correctly at the first attempt. Secondary endpoints included the ability to perform all critical steps correctly at the first attempt, the requisite number of attempts to successfully use the inhaler, the ability to be trained within 15 minutes, and the ability to trigger the K-haler BTI to actuate at the first attempt. Ease of device use and device preference versus patients' usual maintenance inhalers were also assessed. RESULTS AND CONCLUSIONS: At the first attempt, an identical proportion (77.2% [95% confidence interval [CI]: 72.1, 81.8]) of 307 patients performed all pMDI and K-haler BTI handling steps correctly, whereas the corresponding proportions performing all critical steps correctly were 82.4% (95% CIs: 77.7, 86.5) and 87.0% (95% CI: 82.7, 90.5), respectively. For both devices, >90% of patients required only two attempts to master device usage; >99% of patients could be trained to correctly use each device within 15 minutes. Virtually all patients (99.0% [95% CIs: 97.2, 99.8]) were able to successfully trigger the K-haler BTI's dose-release mechanism at first attempt. Ease of use and preference data for FP/FORM pMDI challenged the perceived wisdom that dry powder inhalers are necessarily simpler to use, whereas the corresponding data for FP/FORM K-haler strongly favored this novel BTI over the Turbuhaler®, Accuhaler®, and other pMDIs.

Methoxyflurane Analgesia in Adult Patients in the Emergency Department: A Subgroup Analysis of a Randomized, Double-blind, Placebo-controlled Study (STOP!).

INTRODUCTION: Acute pain remains highly prevalent in the Emergency Department (ED) setting. This double-blind, randomized, placebo-controlled UK study investigated the efficacy and safety of low-dose methoxyflurane analgesia for the treatment of acute pain in the ED in the adult population of the STOP! trial. METHODS: Patients presenting to the ED requiring analgesia for acute pain (pain score of 4-7 on the Numerical Rating Scale) due to minor trauma were randomized in a 1:1 ratio to receive methoxyflurane (up to 6 mL) or placebo (normal saline), both via a Penthrox® (Medical Developments International Limited, Scoresby, Australia) inhaler. Rescue medication (paracetamol/opioids) was available immediately upon request. Change from baseline in visual analog scale (VAS) pain intensity was the primary endpoint. RESULTS: 300 adult and adolescent patients were randomized; data are presented for the adult subgroup (N = 204). Mean baseline VAS pain score was ~66 mm in both groups. The mean change from baseline to 5, 10, 15 and 20 min was greater for methoxyflurane (-20.7, -27.4, -33.3 and -34.8 mm, respectively) than placebo (-8.0, -11.1, -12.3 and -15.2 mm, respectively). The primary analysis showed a highly significant treatment effect overall across all four time points (-17.4 mm; 95% confidence interval: -22.3 to -12.5 mm; p < 0.0001). Median time to first pain relief was 5 min with methoxyflurane [versus 20 min with placebo; (hazard ratio: 2.32; 95% CI: 1.63, 3.30; p < 0.0001)]; 79.4% of methoxyflurane-treated patients experienced pain relief within 1-10 inhalations. 22.8% of placebo-treated patients requested rescue medication within 20 min compared with 2.0% of methoxyflurane-treated patients (p = 0.0003). Methoxyflurane treatment was rated 'Excellent', 'Very Good' or 'Good' by 77.6% of patients, 74.5% of physicians and 72.5% of nurses. Treatment-related adverse events (mostly dizziness/headache) were reported by 42.2% of patients receiving methoxyflurane and 14.9% of patients receiving placebo; none caused withdrawal and the majority were mild and transient. CONCLUSION: The results of this study support the evidence from previous trials that low-dose methoxyflurane administered via the Penthrox inhaler is a well-tolerated, efficacious and rapid-acting analgesic. FUNDING: Medical Developments International (MDI) Limited and Mundipharma Research GmbH & Co.KG. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01420159, EudraCT number: 2011-000338-12.

Effects of low- versus high-dose fluticasone propionate/formoterol fumarate combination therapy on AMP challenge in asthmatic patients: A double-blind, randomised clinical trial.

BACKGROUND: The dose-response relationship between two dose levels of fluticasone/formoterol (flutiform(®), 100/10 µg and 500/20 µg) was evaluated in asthmatic patients. Non-invasive inflammatory markers were used including adenosine monophosphate (AMP) challenge (primary endpoint), and sputum eosinophils and fractional exhaled nitric oxide (FeNO) (secondary endpoints). METHODS: Patients aged ≥18 years with forced expiratory volume in 1 s (FEV1) ≥60% predicted and who required a dose of <60 mg AMP to elicit a 20% drop in FEV1 (AMP PD20) were randomised in this incomplete block, crossover study to receive 2 of 3 treatments b.i.d.: fluticasone/formoterol 500/20 µg (high dose), 100/10 µg (low dose) or placebo, during 2 periods of 28 ± 3 days each, separated by 2-3 weeks. AMP challenges were performed pre-dose and 12 h after last dose at the end of each treatment period. A series of post hoc analyses were performed only in patients allocated to both fluticasone/formoterol doses, who completed the study and had evaluable AMP PD20 data for both treatments ("fluticasone/formoterol subgroup"). Changes in AMP PD20 FEV1, percentage sputum eosinophils and FeNO levels (Day 1 vs Day 28) between treatments were compared by an analysis of covariance (ANCOVA). RESULTS: Sixty-two patients were randomised and 46 completed the study. Fifteen patients received both high- and low-dose fluticasone/formoterol (post hoc subgroup). The difference in AMP PD20 for the overall population was not statistically significant between high- and low-dose fluticasone/formoterol (LS mean fold difference: 1.3; p = 0.489), although both dose levels were superior to placebo: high-dose vs placebo LS mean fold difference: 4.4, p < 0.001; low-dose vs placebo LS mean fold difference: 3.5, p < 0.001. In the post hoc subgroup, the difference in AMP PD20 between the doses was statistically significant in favour of the high-dose (LS mean fold difference: 2.4, p = 0.012). Other inflammatory parameters (sputum eosinophil counts and FeNO) showed small differences and statistically non-significant changes between high- and low-dose fluticasone/formoterol. CONCLUSIONS: A significant dose-response was found between low- and high-dose fluticasone/formoterol in the post hoc subgroup (patients who received both doses), but not in the overall population, with the higher dose demonstrating a greater reduction in airway responsiveness to AMP.

Prolonged-release oxycodone-naloxone for treatment of severe pain in patients with Parkinson's disease (PANDA): a double-blind, randomised, placebo-controlled trial.

BACKGROUND: Pain is a common non-motor symptom of Parkinson's disease. We investigated the analgesic efficacy of prolonged-release oxycodone-naloxone (OXN PR) in patients with Parkinson's disease and chronic, severe pain. METHODS: We did this phase 2 study in 47 secondary care centres in the Czech Republic, Germany, Hungary, Poland, Romania, Spain, and the UK. We enrolled patients with Hoehn and Yahr Stage II-IV Parkinson's disease, at least one type of severe pain, and an average 24-h pain score of at least 6 (assessed on an 11-point rating scale from 0=no pain to 10=pain as bad as you can imagine). Participants were randomly assigned (1:1) with a validated automated system (block size four) to either oral OXN PR or placebo for 16 weeks (starting dose oxycodone 5 mg, naloxone 2·5 mg, twice daily). Patients and investigators were masked to treatment assignment. The primary endpoint was average 24-h pain score at 16 weeks in the full analysis population. This study is registered with EudraCT (2011-002901-31) and ClinicalTrials.gov (NCT01439100). FINDINGS: We enrolled 202 patients; 93 were assigned to OXN PR and 109 to placebo; the full analysis population consisted of 88 patients versus 106 patients. Least squares mean average 24-h pain score at 16 weeks in the full analysis population was 5·0 (95% CI 4·5 to 5·5) in the OXN PR group versus 5·6 (5·1 to 6·0) in the placebo group (difference -0·6, 95% CI -1·3 to 0·0; p=0·058). Similar proportions of patients in each group had adverse events (60/92 [65%] vs 76/109 [70%]), treatment-related adverse events (52/92 [57%] vs 62/109 [57%]), and serious adverse events (5/92 [5%] vs 7/109 [6%]). Treatment-related nausea was more common in the OXN PR group than in the placebo group (16/92 [17%] vs 10/109 [9%]), as was treatment-related constipation (16/92 [17%] vs 6/109 [6%]). INTERPRETATION: The primary endpoint, based on the full analysis population at week 16, was not significant. Nonetheless, the results of this study highlight the potential efficacy of OXN PR for patients with Parkinson's disease-related pain and might warrant further research on OXN PR in this setting. FUNDING: Mundipharma Research.

Efficacy of fluticasone propionate/formoterol fumarate in the treatment of asthma: a pooled analysis.

BACKGROUND: Fluticasone propionate and formoterol fumarate have been combined in a single inhaler (fluticasone/formoterol; flutiform(®)) for the maintenance treatment of asthma. This pooled analysis assessed the efficacy of fluticasone/formoterol versus fluticasone in patients who previously received inhaled corticosteroids. METHODS: Data were pooled from five randomised studies in patients with asthma (aged ≥12 years) treated for 8 or 12 weeks with fluticasone/formoterol (100/10, 250/10 or 500/20 µg b.i.d.; n = 528 delivered via pMDI) or fluticasone alone (100, 250 or 500 µg b.i.d.; n = 527). RESULTS: Fluticasone/formoterol provided significantly greater increases than fluticasone alone in mean morning forced expiratory volume in 1 second (FEV1) from pre-dose at baseline to 2 hours post-dose at study end (least-squares mean [LSM] treatment difference: 0.146L; p < 0.001) and in pre-dose FEV1 from baseline to study end (LSM treatment difference: 0.048 L; p = 0.043). Compared with fluticasone, fluticasone/formoterol provided greater increases in the percentage of asthma control days (no symptoms, no rescue medication use and no sleep disturbance due to asthma) from baseline to study end (LSM treatment difference: 8.6%; p < 0.001), and was associated with a lower annualised rate of exacerbations (rate ratio: 0.71; p = 0.014). CONCLUSIONS: In summary, fluticasone/formoterol provides clinically significant improvements in lung function and asthma control measures, with a lower incidence of exacerbations than fluticasone alone.

Long-term safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate-to-severe chronic cancer pain.

AIM: To evaluate the long-term safety and efficacy of prolonged-release oxycodone/naloxone (OXN PR) and its impact on quality of life (QoL), in patients with moderate-to-severe cancer pain. METHODS: This was an open-label extension (OLE) of a 4 week, randomized, double-blind (DB) study in which patients with moderate-to-severe cancer pain had been randomized to OXN PR or oxycodone PR (OxyPR). During the OLE phase, patients were treated with OXN PR capsules (≤ 20/60 mg/day) for ≤ 24 weeks. Outcome measures included safety, efficacy and QoL. RESULTS: One hundred and twenty-eight patients entered the OLE, average pain scores based on the modified Brief Pain Inventory-Short Form were low and stable over the 24-week period. The improvement in bowel function and constipation symptoms as measured by the Bowel Function Index and patient assessment of constipation in patients treated with OXN PR during the 4-week DB study was maintained. In patients treated with OxyPR during the DB phase, bowel function and constipation symptoms were improved during the OLE. In the DB and in the OLE, health status and QoL were similar for patients treated with OXN PR and OxyPR. There were no unexpected safety or tolerability issues. CONCLUSIONS: In patients with moderate-to-severe cancer pain, long-term use of OXN PR is well tolerated and effective, resulting in sustained analgesia, improved bowel function and improved symptoms of constipation.

Fluticasone/formoterol combination therapy versus budesonide/formoterol for the treatment of asthma: a randomized, controlled, non-inferiority trial of efficacy and safety.

OBJECTIVES: The inhaled corticosteroid fluticasone propionate (fluticasone) and the long-acting ß2 agonist formoterol fumarate (formoterol) have been combined in a single aerosol inhaler fluticasone/formoterol (flutiform(®)). This study compared the efficacy and safety of fluticasone/formoterol with the combination product budesonide/formoterol (Symbicort(®) Turbohaler(®)). METHODS: A randomized, double-blind, double-dummy, multicenter, Phase 3 study comprising a 7- (± 3) day screening, 2-4-week run-in, and 12-week treatment periods. Patients aged ≥ 12 years with moderate to severe persistent asthma for ≥ 6 months before screening and forced expiratory volume in one second (FEV1) 50-80% predicted and ≥ 15% reversibility following salbutamol inhalation were randomized to fluticasone/formoterol 250/10 µg twice daily (n = 140) or budesonide/formoterol 400/12 µg twice daily (n = 139). RESULTS: Fluticasone/formoterol was comparable to budesonide/formoterol with respect to the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. The LS mean treatment difference was -0.044 L, with a lower 95% confidence interval (CI) greater than the pre-defined non-inferiority limit of -0.2 L (95% CI: -0.130, 0.043 L; p < 0.001). Non-inferiority was also demonstrated for the secondary endpoints mean change in FEV1 from baseline (pre-dose) to 2 hours post-dose at Week 12, and discontinuations due to lack of efficacy. Similar results were obtained for both treatment groups for all other secondary endpoints. Fluticasone/formoterol had a good safety profile that was comparable with budesonide/formoterol. CONCLUSIONS: This study demonstrated comparable efficacy of fluticasone/formoterol to budesonide/formoterol in terms of the primary endpoint, change in pre-dose FEV1 from baseline to Week 12. This was supported by comparable results for both treatments for all secondary endpoints.

A randomized, controlled, dose-ranging study investigating single doses of GW406381, naproxen sodium, or placebo in patients with acute pain after third molar tooth extraction.

OBJECTIVES: To evaluate the efficacy and tolerability of 4 doses of GW406381, a cyclooxygenase-2 inhibitor, compared with placebo in a standard model of acute inflammatory pain. METHODS: This randomized, double-blind, placebo-controlled, single-center study compared single doses of GW406381 (10 to 70 mg) or naproxen sodium 550 mg with placebo in patients after extraction of 2 or more partially bony impacted third molar teeth. A total of 300 patients were randomized (50 per group). The primary efficacy variable was the pain relief intensity difference score at each time point, which was calculated as the sum of the pain intensity difference and pain relief categorical scores at each time point. Each treatment was compared with placebo at each time point using an ordered hierarchical approach with closed testing procedures and last observation carried forward imputation methods. RESULTS: Pain relief intensity differences from placebo were statistically significant beginning at 1.5 hours postdosing for GW406381 70 and 50 mg and at 2-hour postdosing for GW406381 25 and 10 mg. The median time to onset of analgesia was 71 minutes for GW406381 50 mg, 72 minutes for GW406381 70 mg, and 36 minutes for naproxen. The median duration of analgesia was 5.9 hours for GW406381 50 mg, 7.9 hours for GW406391 70 mg, and 11.3 hours for naproxen. All treatments were well tolerated. DISCUSSION: GW406381 50 and 70 mg demonstrated clinically meaningful analgesia in this acute pain setting, although the onset of analgesia was greater than 1 hour.