Randomized dose-finding study of batefenterol via dry powder inhaler in patients with COPD

Abstract

Background

Batefenterol is a novel bifunctional muscarinic antagonist β₂-agonist in development for COPD. The primary objective of this randomized, double-blind, placebo-controlled, active comparator, Phase IIb study was to model the dose–response of batefenterol and select a dose for Phase III development.

Patients and methods

Patients aged ≥40 years with COPD and FEV₁ ≥30% and ≤70% predicted normal were randomized equally to batefenterol 37.5, 75, 150, 300, or 600 µg, placebo, or umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg once daily. The primary and secondary endpoints were weighted-mean FEV₁ over 0–6 hours post-dose and trough FEV₁, analyzed by Bayesian and maximum likelihood estimation E_max of dose–response modeling, respectively, on day 42.

Results

In the intent-to-treat population (N=323), all batefenterol doses demonstrated statistically and clinically significant improvements from baseline vs placebo in the primary and secondary endpoints (191.1–292.8 and 182.2–244.8 mL, respectively), with a relatively flat dose–response. In the subgroup reversible to salbutamol, there were greater differences between batefenterol doses. Lung function improvements with batefenterol ≥150 µg were comparable with those with UMEC/VI. Batefenterol was well tolerated and no new safety signals were observed.

Conclusion

Batefenterol 300 µg may represent the optimal dose for Phase III studies.

Keywords:

• bifunctional
• bronchodilator
• dual-pharmacophore
• dose-response
• muscarinic antagonist β₂-agonist

Data availability

Anonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com.

Supplementary materials

Exclusion criteria

Patients were not eligible for inclusion in this study if any of the following criteria applied:

1. Current diagnosis of asthma

2. Respiratory disorders other than COPD, including but not limited to: α–1 antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension unrelated to COPD, and interstitial lung disease. Allergic rhinitis was not exclusionary

3. Other diseases/abnormalities, including uncontrolled hypertension, diabetes, and thyroid disease

4. Presence of hepatitis B surface antigen, positive hepatitis C antibody test result at screening (visit 1) or within 3 months prior to first dose of study treatment

5. Current or chronic history of liver disease and known hepatic or biliary abnormalities (with the exception of Gilbert’s syndrome or asymptomatic gallstones)

6. Current malignancy or previous history of cancer in remission for <5 years prior to visit 1 (localized basal cell or squamous cell carcinoma of the skin that had been resected was not exclusionary); any current or previous history of throat cancer

7. Chest X-ray or computed tomography (CT) scan revealing evidence of clinically significant abnormalities not believed to be due to the presence of COPD. A chest X-ray was taken at visit 1 if a chest X-ray or CT scan was not acquired within 6 months prior to visit 1

8. History of hypersensitivity or allergy to any β-adrenergic receptor agonist, sympathomimetic, anticholinergic/anti-muscarinic receptor antagonist, or lactose/milk protein

9. Diseases preventing use of anticholinergics, for example, narrow-angle glaucoma, prostatic hypertrophy, or bladder neck obstruction

10. Poorly controlled COPD, defined as the occurrence of acute worsening of COPD that was managed with corticosteroid and/or antibiotics or that required treatment prescribed by a physician in the 6 weeks prior to screening (visit 1), or subjects who were hospitalized due to acute worsening of COPD within 12 weeks of visit 1

11. History of more than one COPD exacerbation (moderate or severe) within 12 months prior to visit 1

12. Pneumonia and lower respiratory tract infections requiring the use of antibiotics within 6 weeks prior to visit 1, or pneumonia requiring hospitalization within 12 weeks of visit 1

13. Lung volume reduction surgery within 12 months prior to visit 1

14. Abnormal and clinically significant 12-lead electrocardiogram

15. Clinically significant abnormal findings from clinical chemistry or hematology tests at visit 1

16. Medication prior to spirometry: unable to withhold albuterol/salbutamol for the 4-hour period required prior to spirometry testing at each study visit

17. Use of any of the excluded medications (Table S2)

18. Use of long-term oxygen therapy, described as oxygen therapy prescribed for >12 hours a day. As-needed oxygen use (ie, ≤12 hours/day) was not exclusionary

19. Nebulized therapy: regular use (prescribed for use every day, not for as-needed use) of short-acting bronchodilators (eg, albuterol/salbutamol) via nebulized therapy

20. Pulmonary rehabilitation: participation in the acute phase of a pulmonary rehabilitation program within 4 weeks prior to visit 1. Subjects who were in the maintenance phase of a pulmonary rehabilitation program were not excluded

21. Known or suspected history of alcohol or drug abuse within 2 years prior to visit 1

22. Non-adherence with study procedures

23. Questionable validity of consent, for example, due to a history of psychiatric disease, intellectual deficiency, poor motivation, and so on

24. Affiliation with investigator site

25. Inability to read.

Withdrawal/stopping criteria

Liver chemistry withdrawal/stopping criteria

Liver chemistry withdrawal or stopping criteria are schematically represented in Figure S1.

12-lead electrocardiogram (ECG) withdrawal criteria

For this study, an abnormal and clinically significant 12-lead ECG that would preclude a subject from entering the trial is defined as a 12-lead tracing that is interpreted as, but not limited to, any of the following:

• Sinus bradycardia <45 bpm

  • ○ Note: Sinus bradycardia should be confirmed by two additional readings at least 5 minutes apart

• Sinus tachycardia ≥110 bpm

  • ○ Note: Sinus tachycardia should be confirmed by two additional readings at least 5 minutes apart

• Multifocal atrial tachycardia (wandering atrial pacemaker with rate >100 bpm)

• PR interval >240 ms

• Evidence of Mobitz II second-degree or third-degree atrioventricular block

• Pathological Q waves (defined as wide [>0.04 seconds] and deep [>0.4 mV (4 mm with 10 mm/mV setting)] or >25% of the height of the corresponding R wave, providing the R wave was >0.5 mV [5 mm with 10 mm/mV setting]) appearing in at least two contiguous leads

  • ○ Note: prior evidence (ie, ECG obtained at least prior to 12 months) of pathological Q waves that are unchanged are not exclusionary and the investigator will determine if the subject is precluded from entering the study

• Evidence of ventricular ectopic couplets, bigeminy, trigeminy, or multifocal premature ventricular complexes

• For subjects without complete right bundle branch block: QTc_(F) ≥450 ms or an ECG that is unsuitable for QT measurements (eg, poorly defined termination of the T wave)

• For subjects with complete right bundle branch block: QTc_(F) ≥480 ms or an ECG that is unsuitable for QT measurements (eg, poorly defined termination of the T wave)

  • ○ Note: All potentially exclusionary QT measurements (corrected or uncorrected) should be confirmed by two additional readings at least 5 minutes apart. The final assessment will be based on averaged QTc value of triplicate ECGs

• ST-T wave abnormalities (excluding nonspecific ST-T wave abnormalities)

  • ○ Note: Prior evidence (ie, ECG obtained at least 12 months prior) of ST-T abnormalities that are unchanged are not exclusionary and the investigator will determine if the subject is precluded from entering the study

• Clinically significant conduction abnormalities (eg, Wolff–Parkinson–White syndrome or bifascicular block defined as complete left bundle branch block or complete right bundle branch block with concomitant left fascicular block)

• Clinically significant arrhythmias (eg, atrial fibrillation with rapid ventricular response and ventricular tachycardia).

Statistical analysis

The sample size was determined by simulations and assurance (probability of success) calculations based on Bayesian methods. It was determined that 40 evaluable patients per treatment group would provide a high chance of achieving the study objectives. Statistical assurance was high for hypothesis testing. For example, there was ~90% assurance that the 150-µg dose would provide a 130 mL improvement in FEV₁ over placebo. With 40 patients per group, the half-width of the 95% credible interval for the dose that produced an average improvement of 130 mL versus placebo was approximately within twofold of the estimate. For example, if the estimate was 80 µg, the 95% credible interval was expected to range between 40 and 160 µg; in this case, the 160-µg dose would provide assurance that the average treatment effect would be at least 130 mL greater than placebo.

Summary of safety statistics were prepared for the intent-to-treat (ITT) population. SAS version 9.1 or later was used for analysis.

Bayesian and mixed models repeated measures (MMRM) models

The Bayesian E_max model can accommodate various dose– response curves and has three parameters, encapsulated in the following formula:

$\text{Response}=\mathrm{A}+\left(\mathrm{B}-\mathrm{A}\right)/\left\{1+\exp \left[{\text{LED}}_{50}-\ln \left(\text{dose}\right)\right]\right\}$

where A is the mean response at dose 0; B is the mean response at dose = ∞; and LED₅₀ = ln(ED₅₀) = natural logarithm of the dose that yields a mean response of (A + B)/2.

This formula was used to fit existing Phase IIb data as starting points for the simulations. Bayesian informative priors on the E_max parameters were then constructed directly from the existing data.

Terms fitted to the E_max model included treatment group and baseline FEV₁ value. The E_max dose–response model that best fitted the observed data was used to estimate and predict the change from baseline in weighted-mean FEV₁ over 0–6 hours across the dose range investigated for batefenterol.

Hypothesis testing was performed after the selection of the best fitting model and assessed whether the selected dose would reject a null hypothesis of a treatment effect on FEV₁ of 0, 50, 75, or 130 mL greater than placebo. The secondary efficacy endpoint was analyzed using the maximum likelihood estimation method of E_max dose–response modeling in the ITT population with terms including treatment group and baseline FEV₁.

The MMRM model included terms for treatment group, smoking status, country, sex, inhaled corticosteroid usage, reversibility, and visit (except for serial measures when analysis was performed for each visit separately). The MMRM analysis for trough FEV₁ and FVC included FEV₁ and FVC measurements, respectively, at day 1 (baseline) as covariate, and days 7, 14, 28, and 42 as response. Data were presented as least squares (LS) mean change from baseline with standard error for each treatment group and/or LS mean treatment differences with 95% CIs.

Figure S1 Liver chemistry withdrawal or stopping criteria.

Note: *INR value is not applicable to subjects on anticoagulants.

Abbreviations: INR, international normalized ratio; ULN, upper limit of normal; ALT, alanine aminotransferase.

Table S1 Institutional review boards

Table S2 Excluded medications prior to visit 1 and throughout the study

Acknowledgments

This study was funded and conducted by GlaxoSmithKline (GSK; study number 201012). Medical writing assistance in the form of developing a draft based on author input and editorial assistance was provided by Matthew Robinson, DPhil, and Clare Slater, PhD CMPP, of Fishawack Indicia Ltd, funded by GSK.

The current affiliation of the author Shuyen Ho is UCB BioSciences Inc., Global Statistics and Innovation, Raleigh, NC, USA. The current affiliation of the author Krishna Pudi is Sierra Clinical Research, Las Vegas, NV, USA.

Disclosure

The authors declare the following real/perceived conflicts of interest: C Crim, MLW, C Crawford, CB, and RC-S are GSK employees and hold shares in GSK; SH holds shares in GSK; EDB has received fees from Novartis, Cipla, Sanofi Regeneron, AstraZeneca, ALK, and Boehringer Ingelheim for advisory board membership, fees from Novartis for participation in speakers’ bureau, fees from Vectura and Actelion for consultancy work, fees from Cipla, Menarini, ALK, AstraZeneca, and Boehringer Ingelheim for lectures, and fees from ICON for participation on a study oversight steering committee, and his institution has received funding from Boehringer Ingelheim, Merck, Takeda, GSK, Hoffman le Roche, Actelion, Chiesi, Sanofi-Aventis, Cephalon, TEVA, Novartis, and AstraZeneca for participation in clinical trials. EMK has participated in advisory boards, speaker panels, or received travel reimbursement from Amphastar, AstraZeneca (Pearl), Forest, Novartis, Sunovion, Teva, and Theravance, has participated in medical advisory boards for Mylan and Oriel, and has performed consulting for Oriel and GSK. GJF’s institution has received funding from GSK for participation in clinical trials; KP and IS report no conflicts of interest in this work.

Author contributions

CB contributed to data analysis and interpretation; C Crim, C Crawford, MLW, RC-S, and SH contributed to study design, data analysis, and interpretation; EDB, EMK, IS, GJF, and KP contributed to data acquisition, analysis, and interpretation. All authors were involved at each stage of manuscript preparation including drafting the article or revising it critically for important intellectual content, approved the final version to be published, and agree to be accountable for all aspects of the work.