Colin Reisner

Equivalence considerations for orally inhaled products for local action-ISAM/IPAC-RS European Workshop report.

The purpose of this article is to document the discussions at the 2010 European Workshop on Equivalence Determinations for Orally Inhaled Drugs for Local Action, cohosted by the International Society for Aerosols in Medicine (ISAM) and the International Pharmaceutical Consortium on Regulation and Science (IPAC-RS). The article summarizes current regulatory approaches in Europe, the United States, and Canada, and presents points of consensus as well as ongoing debate in the four major areas: in vitro testing, pharmacokinetic and pharmacodynamic studies, and device similarity. Specific issues in need of further research and discussion are also identified.

Effect of roflumilast and inhaledcorticosteroid/long-acting b2-agonist on chronic obstructive pulmonary disease exacerbations (RE2SPOND): A randomized clinical trial

RATIONALEnModerate and severe exacerbations are incompletely prevented by maximal inhalation therapy in patients with severe chronic obstructive pulmonary disease.nnnOBJECTIVESnTo determine whether roflumilast reduces moderate and/or severe chronic obstructive pulmonary disease exacerbations in patients at risk for exacerbations despite treatment with inhaled corticosteroid/long-acting β2-agonist with or without a long-acting muscarinic antagonist (LAMA).nnnMETHODSnIn this 52-week, phase 4, double-blind, placebo-controlled RE(2)SPOND (Roflumilast Effect on Exacerbations in Patients on Dual [LABA/ICS] Therapy) trial (NCT01443845), participants aged 40 years or older with severe/very severe chronic obstructive pulmonary disease, chronic bronchitis, two or more exacerbations and/or hospitalizations in the previous year, and receiving inhaled corticosteroid/long-acting β2-agonist with or without LAMA daily for 3 or more months were equally randomized to once-daily roflumilast, 500 μg (nu2009=u20091,178), or placebo (nu2009=u20091,176). Stratification was based on LAMA use.nnnMEASUREMENTS AND MAIN RESULTSnAlthough rate of moderate or severe exacerbations per patient per year (primary endpoint) was reduced by 8.5% with roflumilast versus placebo, the between-group difference was not statistically significant (rate ratio, 0.92; 95% confidence interval, 0.81-1.04; Pu2009=u20090.163). However, roflumilast improved lung function, and in a post hoc analysis roflumilast significantly reduced the rate of moderate or severe exacerbations in participants with a history of more than three exacerbations and/or one or more hospitalizations in the prior year. Adverse event-related discontinuations occurred in 11.7% roflumilast-treated and 5.4% placebo-treated participants. Deaths occurred in 2.5% roflumilast and 2.1% placebo participants.nnnCONCLUSIONSnRoflumilast failed to statistically significantly reduce moderate and/or severe exacerbations in the overall population. Roflumilast improved lung function and reduced exacerbations in participants with frequent exacerbations and/or hospitalization history. The safety profile of roflumilast was consistent with that of previous studies. Clinical trial registered with www.clinicaltrials.gov (NCT01443845).

Long-term safety and efficacy of glycopyrrolate/formoterol metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with chronic obstructive pulmonary disease

BACKGROUNDnThe long-term safety and efficacy of a novel Co-Suspension™ Delivery Technology glycopyrrolate (GP)/formoterol fumarate (FF) 18/9.6xa0μg fixed-dose combination metered dose inhaler (GFF MDI) were investigated in a 28-week safety extension study (PINNACLE-3, NCT01970878) of two randomized controlled Phase III trials (PINNACLE-1 and -2; NCT01854645 and NCT01854658) in subjects with moderate-to-very severe chronic obstructive pulmonary disease (COPD).nnnMETHODSnSubjects completing 24 weeks treatment with GFF MDI, GP MDI, FF MDI (all twice-daily) or open-label tiotropium 18xa0μg (once-daily) in PINNACLE-1 or -2 were randomly selected to continue treatment for 28 weeks. The target enrollment for PINNACLE-3 was 850 subjects. Safety and efficacy were evaluated over 52 weeks.nnnRESULTSnOf 3274 subjects randomized to active treatment in PINNACLE-1 or -2, 892 entered PINNACLE-3. Incidences of adverse events, serious adverse events and major adverse cardiovascular events were similar across treatment groups with no unexpected safety findings. For change from baseline in morning pre-dose trough forced expiratory volume in 1xa0s (FEV1), treatment differences for GFF MDI versus GP MDI, FF MDI and open-label tiotropium over 52 weeks were 57, 65 and 25xa0mL, respectively (pxa0≤xa00.0117). Average daily rescue medication use was significantly reduced for GFF MDI versus GP MDI and open-label tiotropium (pxa0≤xa00.0002). Statistically significant improvements were observed with GFF MDI versus monocomponents in Self-Administered Computerized Transition Dyspnea Index focal score, and in St Georges Respiratory Questionnaire total score versus GP MDI.nnnCONCLUSIONSnResults confirmed the long-term safety and tolerability of GFF MDI 18/9.6xa0μg twice-daily in subjects with moderate-to-very severe COPD. Improvements in efficacy endpoints were also sustained over 52 weeks.

The pharmacokinetics of three doses of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler compared with active controls: A Phase I randomized, single-dose, crossover study in healthy adults

The budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) is an inhaled corticosteroid/long-acting muscarinic antagonist/long-acting β2-agonist fixed-dose combination formulated with innovative co-suspension delivery technology that is in clinical development for the treatment of chronic obstructive pulmonary disease (COPD). This randomized, Phase I, single-dose, six-treatment, four-period, crossover study (NCT01980615) examined the pharmacokinetic (PK) and safety profile of three doses of BGF MDI (320/14.4/10 μg [equivalent to budesonide/glycopyrrolate/formoterol fumarate 320/18/9.6 μg], 160/14.4/10 μg and 80/14.4/10 μg), two doses of a budesonide/formoterol fumarate dihydrate fixed-dose combination (BUD/FORM MDI 320/9 μg and 160/9 μg; not using co-suspension delivery technology) and a glycopyrronium/formoterol fumarate dihydrate co-suspension delivery technology MDI (GFF MDI 14.4/10 μg) in healthy volunteers (18-45 years of age). PK parameters included area under the plasma concentration-time curve from 0 to 12 h (AUC0-12), AUC up to the last measurable concentration (AUC0-t), maximum plasma concentration (Cmax) and time to maximum plasma concentration (tmax). Safety was monitored throughout the study. Of 84 subjects randomized, 76 completed the study. BGF MDI 320/14.4/10 μg was bioequivalent to BUD/FORM MDI 320/9 μg for budesonide for Cmax, AUC0-12 and AUC0-t (primary objective). Dose proportionality was observed for the budesonide component between BGF MDI 80/14.4/10 μg and BGF MDI 160/14.4/10 μg, and between BGF MDI 160/14.4/10 μg and BGF MDI 320/14.4/10 μg. Systemic exposure to glycopyrronium and formoterol after BGF MDI 320/14.4/10 μg treatment was similar to GFF MDI 14.4/10 μg. The rate of adverse events was 3.7-17.9% across treatments without any serious adverse events. In conclusion, BGF MDI 320/14.4/10 μg had a similar budesonide PK profile to BUD/FORM MDI 320/9 μg. No PK drug-drug interactions were observed when budesonide was added to glycopyrronium and formoterol fumarate dihydrate. These data support the use of budesonide 320 μg and 160 μg in future clinical trials of BGF MDI in COPD.

Triple therapy with budesonide/glycopyrrolate/formoterol fumarate with co-suspension delivery technology versus dual therapies in chronic obstructive pulmonary disease (KRONOS): a double-blind, parallel-group, multicentre, phase 3 randomised controlled trial

BACKGROUNDnInhaled corticosteroids have been used in patients with chronic obstructive pulmonary disease (COPD), but the potential benefits of their use in triple therapy are not well known. We aimed to compare the efficacy of a triple therapy with corresponding dual therapies in symptomatic patients with moderate to very severe COPD, without a requirement for a history of exacerbations.nnnMETHODSnIn this double-blind, parallel-group, multicentre phase 3 randomised controlled trial, we recruited patients from hospitals and care centres in Canada, China, Japan, and the USA. Eligible patients were 40-80 years of age, were current or former smokers (with a smoking history of ≥10 pack-years), had an established clinical history of COPD, and were symptomatic for COPD, despite receiving two or more inhaled maintenance therapies for at least 6 weeks before screening. We randomly assigned patients (2:2:1:1) using an interactive web response system to receive budesonide/glycopyrrolate/formoterol fumarate metered-dose inhaler 320/18/9·6 μg (BGF MDI), glycopyrrolate/ formoterol fumarate metered-dose inhaler 18/9·6 μg (GFF MDI), budesonide/formoterol fumarate metered-dose inhaler 320/9·6 μg (BFF MDI), or open-label budesonide/formoterol fumarate dry-powder inhaler 400/12 μg (BUD/ FORM DPI). Primary endpoints for the Europe/Canada statistical analysis approach were FEV1 area under the curve from 0-4 h (AUC0-4) for BGF MDI versus BFF MDI and BGF MDI versus BUD/FORM DPI over 24 weeks; and change from baseline in morning pre-dose trough FEV1 for BGF MDI versus GFF MDI and non-inferiority of BFF MDI versus BUD/FORM DPI (margin of -50 mL from lower bound of 95% CI) over 24 weeks. Comparisons with BUD/FORM DPI were made for the Europe/Canada statistical analysis approach only. This study is registered with ClinicalTrials.gov, number NCT02497001.nnnFINDINGSnBetween Aug 20, 2015, and Jan 5, 2018, 3047 patients were screened from 215 sites, and 1902 were randomly assigned to receive BGF MDI (n=640), GFF MDI (n=627), BFF MDI (n=316), or BUD/FORM DPI (n=319). Over 24 weeks, BGF MDI significantly improved FEV1 AUC0-4 versus BFF MDI (least squares mean difference 104 mL, 95% CI 77 to 131; p<0·0001) and BUD/FORM DPI (91 mL, 64 to 117; p<0·0001). BGF MDI also significantly improved pre-dose trough FEV1 versus GFF MDI (22 mL, 4 to 39; p=0·0139) and was non-inferior to BUD/FORM DPI (-10 mL, -36 to 16; p=0·4390). At week 24, patients in the BGF MDI group had a significantly improved FEV1 AUC0-4 compared with patients receiving BFF MDI (116 mL, 95% CI 80 to 152; p<0·0001); there was a non-significant improvement in the change from baseline in morning pre-dose trough FEV1 at week 24 versus GFF MDI (13 mL, -9 to 36 mL; p=0·2375). The most common treatment-emergent adverse events were nasopharyngitis (n=49 [8%] in the BGF MDI group; n=41 [7%] in the GFF MDI group; n=26 [8%] in the BFF MDI group; and n=30 [9%] in the BUD/FORM DPI group) and upper respiratory tract infection (n=65 [10%]; n=38 [6%]; n=18 [6%]; and n=22 [7%]). Pneumonia incidence was low (<2%) and similar across treatments. There were two treatment-related deaths, both in the GFF MDI group.nnnINTERPRETATIONnBGF MDI was efficacious, well tolerated, and could be a more appropriate treatment than the corresponding dual therapies for symptomatic patients with moderate to very severe COPD, irrespective of exacerbation history.nnnFUNDINGnPearl-a member of the AstraZeneca Group.

24-h bronchodilation and inspiratory capacity improvements with glycopyrrolate/formoterol fumarate via co-suspension delivery technology in COPD

BackgroundSymptoms of chronic obstructive pulmonary disease may vary throughout the day and it is important that therapeutic approaches provide 24-h symptom control. We report the results of two phase IIIb crossover studies, PT003011 and PT003012, investigating the 24-h lung function profile of GFF MDI (glycopyrrolate/formoterol fumarate 18/9.6 μg delivered using innovative co-suspension delivery technology) administered twice daily.MethodsPatients with moderate-to-very severe chronic obstructive pulmonary disease received 4 weeks’ treatment with each of GFF MDI, placebo MDI, and open-label tiotropium (PT003011 only). Lung function was assessed over 24 h on day 29 of each treatment period. The primary outcome was forced expiratory volume in 1 second area under the curve from 0 to 24 h (FEV1AUC0–24). Other outcomes included change from baseline in average daily rescue medication use over the treatment period. In addition, we conducted a post-hoc analysis of data pooled from both studies to further characterize the effect of GFF MDI on inspiratory capacity.ResultsGFF MDI treatment significantly increased FEV1AUC0–24 versus placebo in studies PT003011 (n = 75) and PT003012 (n = 35) on day 29 (both studies p < 0.0001), with similar improvements in FEV1AUC versus placebo for hours 0–12 and 12–24. In PT003011, improvements with GFF MDI versus tiotropium in FEV1AUC were greater during hours 12–24 compared to 0–12 h. GFF MDI treatment also resulted in a significant reduction in rescue medication use versus placebo (−0.84 [p<0.0001] and −1.11 [p=0.0054] puffs/day in PT003011 and PT003012, respectively), and versus tiotropium in PT003011 (−0.44 [p=0.017] puffs/day). A post-hoc pooled analysis showed patients treated with GFF MDI were more likely to achieve a >15% increase from baseline in inspiratory capacity than patients treated with placebo or tiotropium (72.1%, 19.0% and 47.0% of patients, respectively after the evening dose on day 29). There were no significant safety/tolerability findings.ConclusionsGFF MDI significantly improved 24-h lung function versus placebo in patients with moderate-to-very severe chronic obstructive pulmonary disease, with similar benefits in the second 12-h period compared to the first, supporting twice-daily dosing of GFF MDI.Trial registrationPearl Therapeutics, Inc.; www.clinicaltrials.gov; NCT02347072 and NCT02347085. Registered 21 January 2015.

Baseline Symptom Score Impact on Benefits of Glycopyrrolate/Formoterol Metered Dose Inhaler in COPD

BACKGROUND: The clinical severity of COPD is currently categorized by symptom burden and exacerbation risk. Previous 24‐week phase III trials (NCT01854645 and NCT01854658) that demonstrated better improvement of lung function with glycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) (an MDI fixed‐dose of GFF 18/9.6 &mgr;g) over individual monocomponent MDIs included a cross‐section of patients with moderate to very severe airflow limitation and a broad range of COPD symptoms. METHODS: These post hoc analyses of pooled data investigated whether baseline symptom burden, assessed using the COPD Assessment Test (CAT) score, impacted GFF MDI‐associated improvements in lung function, health status, rescue medication use, and exacerbation risk. RESULTS: In 3,699 patients, improvement in FEV1 at week 24 between the GFF MDI and monocomponent MDIs and a placebo MDI was similar in magnitude regardless of baseline CAT score. In contrast, the magnitude of mean difference in the St. Georges Respiratory Questionnaire total score for GFF MDI vs monocomponent MDIs and the placebo MDI increased with increasing baseline CAT scores. Likewise, reduced rescue medication use and lower exacerbation risk were more pronounced in GFF MDI groups with a higher baseline symptom burden. CONCLUSIONS: Beneficial effects of GFF MDI on health status, rescue medication use, and exacerbation risk in symptomatic patients with COPD increased as a function of baseline symptom burden, whereas lung function benefits were independent. These data suggest a greater clinical benefit from dual bronchodilators in symptomatic patients than in patients without symptoms. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01854645 and NCT01854658; URL: www.clinicaltrials.gov.

Cardiovascular safety profile of a fixed-dose combination of glycopyrrolate and formoterol fumarate delivered via metered dose inhaler using co-suspension delivery technology.

BACKGROUNDnGlycopyrrolate/formoterol fumarate (GFF) metered dose inhaler (MDI) is a fixed-dose combination of the long-acting muscarinic antagonist (LAMA), glycopyrrolate (GP), and the long-acting β2-agonist (LABA), formoterol fumarate (FF), delivered via metered dose inhaler using innovative co-suspension delivery technology. Here we report the results of two studies that examined the cardiovascular safety of GFF MDI.nnnMETHODSnThe thorough QT (TQT) study was a Phase I, randomized, double-blind, single-dose, crossover study to assess GFF MDI 18/9.6 (Bevespi Aerosphere®), GFF MDI 144/38.4 and GP MDI 144u202fμg, compared with placebo MDI and open-label moxifloxacin 400u202fmg (active control) in healthy volunteers (PT003009). The cardiovascular safety study in patients with chronic obstructive pulmonary disease (COPD) was a Phase IIb, randomized, multicenter, double-blind, 14-day dosing, parallel-group study to evaluate GFF MDI 36/9.6, GP MDI 36 and FF MDI 9.6u202fμg compared with open-label FF dry powder inhaler (DPI; Foradil® Aerolizer®) 12u202fμg, in patients with moderate-to-severe COPD (PT003003 [NCT01349803]).nnnRESULTSnSeventy healthy volunteers were randomized in the TQT study. GFF MDI 144/38.4, GFF MDI 18/9.6 and GP MDI 144u202fμg all met the confidence interval-based criteria for negative QT prolongation potential. In the study in patients with COPD, 237 subjects were randomized and treated. GFF MDI 36/9.6, GP MDI 36, and FF MDI 9.6u202fμg did not result in clinically meaningful changes from baseline in 24-h mean heart rate at Day 14 (primary endpoint) or in any of the other Holter monitoring endpoints at Day 14, compared with FF DPI 12u202fμg.nnnCONCLUSIONSnNo clinically significant effects on cardiovascular safety occurred at therapeutic or supratherapeutic doses of GFF MDI, apart from a small and transient increase in heart rate following supratherapeutic dose of GFF MDI 144/38.4u202fμg. Furthermore, there were no unexpected safety findings reported in either healthy volunteers or patients with COPD.

Pharmacokinetics of Co‐Suspension Delivery Technology Budesonide/Glycopyrronium/Formoterol Fumarate Dihydrate (BGF MDI) and Budesonide/Formoterol Fumarate Dihydrate (BFF MDI) Fixed‐Dose Combinations Compared With an Active Control: A Phase 1, Randomized, Single‐Dose, Crossover Study in Healthy Adults

This randomized, phase 1, single‐dose, crossover study (NCT02189304) compared the 12‐hour pharmacokinetic (PK) and safety profiles of budesonide/glycopyrronium/formoterol fumarate dihydrate metered dose inhaler (BGF MDI) 320/14.4/10 μg and budesonide/formoterol fumarate dihydrate (BFF) MDI 320/10 μg (both formulated using innovative co‐suspension delivery technology) to an active comparator (budesonide/formoterol fumarate dihydrate dry powder inhaler [BUD/FORM DPI] 320/9‐μg delivered dose) in healthy adults. The potential for PK interaction between glycopyrronium and budesonide/formoterol within BGF MDI was assessed. Of 72 subjects randomized, 59 completed treatment. Systemic budesonide exposure (primary objective) based on area under the plasma drug concentration‐time curve 0‐12 hours (AUC0‐12; % coefficient of variation) was 1598.38 (49.7), 1657.09 (50.4), and 1276.75 (70.4) pg·h/mL for BGF MDI, BFF MDI, and BUD/FORM DPI, respectively; and formoterol exposure (AUC0‐12 [% coefficient of variation]) was 39.16 (45.9), 39.53 (40.5), and 23.24 (59.2) pg·h/mL, respectively. BGF MDI and BFF MDI were bioequivalent for budesonide and formoterol. All treatments were well tolerated. While systemic exposure to budesonide and formoterol was higher for BGF MDI and BFF MDI than for BUD/FORM DPI, there were no appreciable differences in the incidence of pharmacologically predictable adverse events. This, coupled with the absence of PK interactions, suggests the BGF MDI safety profile will be comparable to BUD/FORM DPI.

A phase IIb randomized, chronic-dosing, incomplete block, cross-over study of glycopyrronium, delivered via metered dose inhaler, compared with a placebo and an active control in patients with moderate-to-severe COPD

BackgroundLong-acting muscarinic antagonist (LAMA) and long-acting β2-agonist (LABA) bronchodilators are key to the pharmacologic treatment of chronic obstructive pulmonary disease (COPD). This Phase IIb study investigated the safety and efficacy of four doses of the LAMA glycopyrronium (GP) delivered using co-suspension delivery technology via metered dose inhaler (MDI). The study was part of a wider clinical trial program performed to determine the optimal dose of GP MDI, the LABA formoterol fumarate dihydrate (FF) MDI, and glycopyrronium/formoterol fumarate dihydrate (GFF) MDI fixed-dose combination to be taken forward into Phase III studies.MethodsIn this randomized, double-blind, 7-day chronic-dosing, three-period incomplete block, cross-over study, patients with moderate-to-severe COPD received two of the four doses of GP MDI (28.8xa0μg, 14.4xa0μg, 7.2xa0μg, and 3.6xa0μg) twice daily (BID), and either placebo MDI BID or open-label ipratropium MDI 34xa0μg four times daily. The primary efficacy endpoint was forced expiratory volume in 1xa0s (FEV1) area under the curve from 0 to 12xa0h (AUC0–12) relative to baseline on Day 7. Secondary and exploratory efficacy endpoints were assessed on Days 1 and 7. Safety and tolerability were evaluated throughout the study.ResultsAll GP MDI treatments were superior to placebo MDI for the primary efficacy endpoint (all pu2009<u20090.0001). However, only GP MDI 28.8xa0μg and 14.4xa0μg demonstrated statistical superiority to placebo MDI for all secondary efficacy endpoints analyzed in this study, with the exception of GP MDI 14.4xa0μg versus placebo MDI for the proportion of patients achieving ≥12% improvement in FEV1. No nominally significant differences were observed between GP MDI 28.8xa0μg and GP MDI 14.4xa0μg for any of the endpoints. All doses of GP MDI were well tolerated, with no unexpected safety findings.ConclusionsThis study indicated that there was no advantage of GP MDI 28.8xa0μg compared with GP MDI 14.4xa0μg. It therefore added to the evidence from the Phase I/II clinical trial program, which identified GP MDI 14.4xa0μg as the most appropriate dose for use in the Phase III clinical studies.Trial registrationClinicalTrials.gov (NCT01350128). Registered May 09, 2011.