Patrick Darken

Efficacy and Safety of Glycopyrrolate/Formoterol Metered Dose Inhaler Formulated Using Co-Suspension Delivery Technology in Patients With COPD

Background: Long‐acting muscarinic antagonist (LAMA)/long‐acting &bgr;2‐agonist (LABA) combinations are a treatment option for patients with COPD who continue to have symptoms despite treatment with a LAMA or a LABA alone. The Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate‐to‐Very Severe COPD (PINNACLE‐1) (NCT01854645) and the Multi‐Center Study to Assess the Efficacy and Safety of PT003, PT005, and PT001 in Subjects with Moderate‐to‐Very Severe COPD (PINNACLE‐2) (NCT01854658) trials investigated the efficacy and safety of a novel glycopyrrolate [GP]/formoterol [FF] 18/9.6‐&mgr;g (GFF) metered dose inhaler (MDI) formulated using the Co‐Suspension Delivery Technology in patients with moderate‐to‐very severe COPD. Methods: These two phase III trials took place over 24 weeks and were randomized, double blind, and placebo controlled; 2,103 and 1,615 patients (40–80 years of age), respectively, were randomized. Patients received GFF MDI, GP MDI 18 &mgr;g, FF MDI 9.6 &mgr;g, or placebo MDI (all twice daily), or tiotropium 18 &mgr;g dry powder inhaler (once daily in PINNACLE‐1 only [open‐label active comparator]). Efficacy and safety were assessed. Results: At week 24, differences in change from baseline in the morning predose trough FEV1 for GFF MDI vs placebo MDI, GP MDI, and FF MDI were 150 mL, 59 mL, and 64 mL in PINNACLE‐1 (all P < .0001) and 103 mL, 54 mL, and 56 mL in PINNACLE‐2 (all P < .001), respectively. There were no significant safety findings (incidence of adverse events was similar between treatment arms). Conclusions: We conclude that GFF MDI 18/9.6 &mgr;g demonstrated superiority over placebo and monocomponent MDIs and was well tolerated, thus providing an additional treatment option for patients with moderate‐to‐very severe COPD. Trial Registry: ClinicalTrials.gov; No.: NCT01854645 and No. NCT01854658; URL: www.clinicaltrials.gov.

Efficacy of Formoterol Fumarate Delivered by Metered Dose Inhaler Using Co-Suspension™ Delivery Technology Versus Foradil® Aerolizer® in Moderate-To-Severe COPD: A Randomized, Dose-Ranging Study

Background: Co-Suspension™ Delivery Technology offers a novel pharmaceutical platform for inhaled drug therapy. This randomized, double-blind, placebo-controlled, single-dose study (NCT01349868) evaluated the efficacy of a range of doses for formoterol fumarate (FF) delivered using Co-Suspension delivery technology via a pressurized metered dose inhaler (MDI) versus placebo in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). Secondary objectives included determination of non-inferior efficacy and systemic exposure compared with open-label Foradil® 12 μg (Foradil® Aerolizer®; formoterol fumarate dry powder inhaler). Methods: Patients received each of the 6 study treatments (FF MDI [7.2, 9.6 and 19.2μg], placebo MDI and open-label Foradil® [12 and 24µg]), separated by 3-10 days. Spirometry was performed 60 and 30 minutes prior to and at regular intervals up to 12 hours post-administration of study drug. The primary outcome measure was the change in forced expiratory volume in 1 second (FEV1) area under the curve between 0 and 12 hours (AUC0-12) relative to test day baseline. Results: A total of 50 patients were randomized to study treatment sequences. All doses of FF MDI demonstrated superiority to placebo (p<0.0001) and non-inferiority to Foradil® 12μg, on bronchodilator outcome measures. No serious adverse events were reported during the study. Conclusions: This study demonstrates non-inferiority of bronchodilator response and bioequivalent exposure of FF MDI 9.6μg to Foradil® 12μg, with both agents exhibiting a similar safety profile in patients with moderate-to-severe COPD. This study supports the selection of FF MDI 9.6µg for further evaluation in Phase III trials.

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.

Design and Analysis of Studies to Assess the Effect of Inhaled Corticosteroids on Growth

Assessment of child growth is problematic: growth is nonlinear in the long-term, and unpredictable in the short-term; growth is subject to a number of environmental as well as genetic influences; and growth is difficult to measure reliably. The potential for growth delay as an effect of asthma is established, although it has proved difficult to quantify how great an impact this has on height, growth velocity, or final attained height. In the treatment of asthmatic children, there remain uncertainties as to the effect of inhaled corticosteroids on growth, given the great number of factors affecting growth. In this paper we present recommendations for the design and analysis of trials to assess the effect of regular treatment with inhaled corticosteroids on growth in asthmatic children. Design recommendations are articulated for study duration, entry criteria, other factors that may affect growth, measuring height, measuring growth, study objectives, and considerations relating to confounding between treatment allocation and the effect of the disease on growth. Special attention is given to analyses that address both the intra-subject correlation arising from multiple measurements in longitudinal studies of growth and the potential bias in treatment comparisons due to dropouts, especially those due to treatment failure.

Efficacy, safety, and pharmacokinetics of budesonide/formoterol fumarate delivered via metered dose inhaler using innovative co-suspension delivery technology in patients with moderate-to-severe COPD

Purpose This study investigated the efficacy, safety, and pharmacokinetics of the inhaled corticosteroid/long-acting β2-agonist fixed-dose combination budesonide/formoterol fumarate (BFF) metered dose inhaler (MDI), compared with the monocomponents budesonide (BD) MDI and formoterol fumarate (FF) MDI, in patients with moderate-to-severe COPD. Materials and methods In this Phase IIb, randomized, double-blind, four-period, five-treatment, incomplete-block, crossover study (NCT02196077), all patients received BFF MDI 320/9.6 μg and FF MDI 9.6 μg, and two of either BFF MDI 160/9.6 μg, BFF MDI 80/9.6 μg, or BD MDI 320 μg twice daily for 28 days. The primary efficacy endpoint was forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29. Secondary efficacy endpoints included additional lung function assessments, and evaluation of dyspnea and rescue medication use. Safety was monitored throughout. The systemic exposure to budesonide and formoterol was assessed on Day 29. Results Overall, 180 patients were randomized. For forced expiratory volume in 1 second area under the curve from 0 to 12 hours on Day 29, all BFF MDI doses showed significant improvements versus BD MDI 320 μg (least squares mean differences 186–221 mL; all p<0.0001), and BFF MDI 320/9.6 μg demonstrated a significant improvement versus FF MDI 9.6 μg (least squares mean difference 56 mL; p=0.0013). Furthermore, all BFF MDI doses showed significant improvements versus BD MDI 320 μg for all lung function, dyspnea, and rescue medication use secondary efficacy endpoints. All BFF MDI doses were well tolerated, and the safety profile was not substantially different from the monocomponents. There was no evidence of clinically meaningful pharmacokinetic interactions when budesonide and formoterol were formulated together in BFF MDI. Conclusion The findings presented here confirm that BFF MDI 320/9.6 μg is an appropriate dose to take forward into Phase III studies in patients with COPD.

Randomized study of the effects of Aerochamber Plus ® Flow-Vu ® on the efficacy, pharmacokinetics and safety of glycopyrronium/formoterol fumarate dihydrate metered dose inhaler in patients with chronic obstructive pulmonary disease

OBJECTIVES This study compared the efficacy, pharmacokinetics (PK), and safety of GFF MDI (Bevespi Aerosphere®), a fixed-dose combination of glycopyrronium and formoterol fumarate dihydrate (14.4/10 μg) delivered by a metered dose inhaler (MDI) formulated using innovative co-suspension delivery technology, in patients with moderate-to-very severe chronic obstructive pulmonary disease (COPD) with and without the Aerochamber Plus® Flow-Vu® valved holding chamber (VHC). METHODS In this multicenter, open-label, crossover, Phase III study (NCT02454959), patients were randomized to receive GFF MDI 14.4/10 μg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 μg) twice daily for 7 days with and without the VHC. The primary endpoint was forced expiratory volume in 1 s area under the curve from 0 to 12 h (FEV1 AUC0-12) on Day 8. Steady state PK parameters for glycopyrronium and formoterol (AUC0-12, peak concentration [Cmax] and time to peak concentration [tmax]) were estimated from 12-h plasma concentration time data on Day 8. Safety and tolerability were also assessed throughout. RESULTS Eighty patients were randomized. On Day 8, the ratio (90% confidence interval [CI]) of least squares mean (LSM) FEV1 AUC0-12 for GFF MDI with VHC (LSM = 1538 mL; n = 67) versus without VHC (LSM = 1516 mL; n = 68) was 101.4% (100.1, 102.7). PK parameters were comparable overall with a slightly higher exposure to glycopyrronium with the VHC. The AUC0-12 geometric LSM ratio (90% CI) for GFF MDI with versus without VHC was 115.99% (99.74, 134.89) for glycopyrronium and 96.66% (86.69, 107.78) for formoterol. GFF MDI with and without VHC were well tolerated with a similar adverse event profile. CONCLUSIONS The magnitude of bronchodilatory effect was similar with and without a VHC following GFF MDI treatment. This, together with the PK and safety profiles, supports the use of the VHC with GFF MDI for the maintenance treatment of COPD, which could be particularly useful for patients who have difficulty with the coordination of an MDI.

Efficacy and safety of four doses of glycopyrrolate/formoterol fumarate delivered via a metered dose inhaler compared with the monocomponents in patients with moderate-to-severe COPD

Purpose To determine the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 36/9.6, 36/7.2, 18/9.6, 9/9.6 µg) using innovative co-suspension delivery technology, compared with glycopyrrolate (GP) MDI 36 µg and formoterol fumarate (FF) MDI 9.6 µg, in patients with moderate-to-severe COPD. Methods In this Phase IIb, randomized, double-blind, balanced incomplete-block, two-period, cross-over study (NCT01349816), patients received treatment twice-daily for 7 days. The primary efficacy endpoint was forced expiratory volume in 1 second (FEV1) area under the curve from 0 to 12 hours (AUC0–12) on Day 7. Secondary efficacy endpoints were peak change from baseline in FEV1 through 2 hours; time to onset of action (≥10% improvement in mean FEV1); proportion of patients achieving ≥12% improvement in FEV1 on Day 1; peak change from baseline in inspiratory capacity (IC) on Days 1 and 7; change from baseline in morning pre-dose FEV1; peak change from baseline in FEV1 through 6 hours; and change from baseline in mean evening 12-hour post-dose trough FEV1 on Day 7. Safety was assessed. Results All 185 randomized patients received treatment. All doses of GFF MDI significantly improved the primary endpoint compared with GP MDI 36 µg (all P≤0.0137). For peak change in FEV1 and IC and time to onset of action secondary endpoints, ≥2 doses of GFF MDI demonstrated superiority to GP MDI 36 µg. No significant differences were observed between GFF MDI and FF MDI 9.6 µg for primary and secondary endpoints. The incidence of adverse events was similar between treatments. Conclusion While all doses of GFF MDI were superior to GP MDI 36 µg for the primary end-point, in this study neither superiority of GFF MDI to FF MDI 9.6 µg nor a clear dose-response was observed. All treatments were well tolerated with no unexpected safety findings.

Erratum: A randomized, seven-day study to assess the efficacy and safety of a glycopyrrolate/formoterol fumarate fixed-dose combination metered dose inhaler using novel Co-Suspension™ Delivery Technology in patients with moderate-to-very severe chronic obstructive pulmonary disease. [Respir Res. 18, 1 (2017), (8)] DOI: 10.1186/s12931-016-0491-8

Erratum Upon Publication of the original article [1] several discrepancies were highlighted in the following sections; Results, Table 1, Table 2 and Fig. 3. These errors have since been acknowledged and corrected in this erratum The first sentence in the subsection “Baseline characteristics” originally read: Patients’ baseline and demographic characteristics are shown in Table 1 (mITT population). This should read: Patients’ baseline and demographic characteristics are shown in Table 1. The header of Table 1 read: Baseline demographics (mITT population) This should read as: Baseline demographics (ITT population) It was noticed that Table 2 contained an error. In Table 2, data row 2, the footnote symbol ‘c’ was erroneously included in the third column. The footnote symbol ‘c ‘should be placed in the second column in this row. The corrected Table 2 is shown below. It was noticed that in Fig. 3b, the error bar on the 4th data point (AUCinf ) was incorrectly given. The error bar

Benefit of FDC budesonide (BUD) and formoterol fumarate (FF) FDC delivered by a novel MDI co-suspension technology (BFF MDI), in patients (pts) with moderate-to-severe COPD

Background Combining an ICS with bronchodilator therapy is recommended for COPD pts not adequately controlled by long-acting bronchodilators. We assessed the efficacy and safety of BFF MDI in moderate-to-severe COPD pts. Methods In this Phase IIb, multicentre, double-blind, incomplete-block, crossover trial in moderate-to-severe COPD, pts were randomised to BFF MDI (320/9.6 μg, 160/9.6 μg and 80/9.6 μg), BUD MDI 320 μg and FF MDI 9.6 μg, twice daily, for 28 days, followed by washout of 14–21 days (NCT02196077). The primary endpoint was FEV1 AUC0–12h on Day 29. Results 180 pts (mean age 62 years, 47% male, mean screening post-bronchodilator FEV1 53% of predicted) participated. All three doses of BFF MDI significantly increased FEV1 AUC0–12h on Day 29, and morning pre-dose trough FEV1 and peak change from baseline in FEV1 over 28 days vs BUD MDI (Table). Only BFF MDI 320/9.6 μg led to a significant difference vs FF MDI in all of these endpoints; numerically lower changes were observed with the two lower BFF MDI doses. Conclusion BFF MDI 320/9.6 μg improved lung function vs BUD and FF MDIs in moderate-to-severe COPD pts, while few diffrerences were seen between BFF MDI 160/9.6 μg and 80/9.6 μg, and the monocomponent MDIs. These data confirm 320/9.6 μg as the most appropriate dose of BFF MDI to progress into Phase III studies.