The Efficacy, Tolerance and Acceptance of a New Fixed-Dose Salmeterol and Fluticasone Propionate Dry-Powder Inhaler—Salflumix Easyhaler^® in COPD Patients in the Daily Clinical Practice

Round 1

Reviewer 1 Report

<Major Comments>

Materials and Methods:

1. This study was referred to as a post-authorization, non-interventional, multicenter, investigator-initiated study of the Salflumix Easyhaler^®. Please confirm whether the research design of this study was a prospective study or a retrospective study.

2. The authors stated in the text that the permission of the bioethical committee was not required. However, all studies conducted in patients require IRB approval. An explanation of this and presentation of the approval number are required.

 

Results:

3. As mentioned by the authors in the INTRODUCTION, the use of ICS in COPD patients is indicated for use in patients with moderate to very severe COPD with repeated exacerbations according to the GOLD guidelines. In Table 1, GOLD A & B account for a much larger number than GOLD C & D in both groups (“newly diagnosed” and “switched”). This needs confirmation and explanation.

4. Patients enrolled in this study were evaluated by visiting the hospital 3 consecutive appointments, approximated 6 weeks apart (in the METHODS section). However, the period of Salflumix Easyhaler^® use during the study period was analyzed as 86±30 days. Table 1 shows that 90.5% of all patients used Salflumix Easyhaler^® for 2-4 weeks. It seems too short compared to what was mentioned in the METHODS section.

 

Discussion:

5. Since the study period was very short, it would be considered very difficult to confirm the frequency of exacerbations during this period. However, the authors calculated the frequency (43.3%) of exacerbations over 86±30 days with the frequency (67.7%) of exacerbations over the past 12 months. I wonder how it was converted and if it is possible.

 

<Minor Comments>

Line 47: … Salflumix Easyhaler^® (Orion Pharma),… à (Orion Pharma, Warsaw, Poland)

Line 68: [for review 7] à [7]

Line 77: Salflumix Easyhaler^® (Orion Pharma, Warsaw, Poland) à Salflumix Easyhaler^®

Line 82: This IIS study à This IIS

Line 108: good very good. à good, and very good.

Line 117, 120: pts à points

Line 168, 173: (p<0.001 for trend) à (p<0.001)

Line 171, 173, 180: - Table 2 à (Table 2)

Line 278-279: ‘I do not have any COI with the mentioned company, but it would be better to delete this mentioned part.’

Author Response

1. This study was referred to as a post-authorization, non-interventional, multicenter, investigator-initiated study of the Salflumix Easyhaler®. Please confirm whether the research design of this study was a prospective study or a retrospective study.

Ad 1. It was a prospective study. Such information was added to the methodology section.

2. The authors stated in the text that the permission of the bioethical committee was not required. However, all studies conducted in patients require IRB approval. An explanation of this and presentation of the approval number are required.

Ad 2.

 

According to the local regulations confirmed in the opinion of the legal office the monitoring of efficacy and safety of registered drugs used in line with the summary of product characteristics does not require the permission of the bioethics committee. Information on post-authorisation studies (PAS) that are not clinical trials (i.e. outside the scope of Directive 2001/20/EC) should be registered in the EU PAS provided by European Medicines Agency (EMA). Register has a focus on observational research, and its purpose is to support transparency on post-authorisation studies (PAS), whether they are initiated, managed or financed by a marketing authorisation holder voluntarily or pursuant to an obligation. Our study was registered in the EU PAS Register (EU PAS 36156). The European Union electronic Register of Post-Authorisation Studies (EU PAS Register) is a publicly available register of non-interventional post-authorisation studies. The Register has a focus on observational research, and its purpose is to: increase transparency, reduce publication bias, promote the exchange of information and facilitate collaboration among stakeholders, including academia, sponsors and regulatory bodies, and ensure compliance with EU pharmacovigilance legislation requirements.

This information was provided in the methodology section and in Institutional Review Board Statement: ‘Not applicable. Monitoring of the authorized medical product efficacy in daily clinical practice was in line with the requirements of Directive 2001/83/EC of the European Parliament with further actualizations.’

The full legal opinion is provided below:

Monitoring of the authorized medical product Salflumix Easyhaler^® efficacy and in daily clinical practice (real life) was in line with the requirements of Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use (OJ I. 311 of 28.11.2001, p. 67 as amended), Directive 2001/83/EC and  Act of 6 September 2001 Pharmaceutical Law (Journal of Laws of 2001, No. 126, item 1381, as amended), ART 1(15) and Act of 12 May 2011 on the reimbursement of drugs and foodstuffs for particular nutritional uses and medical devices (Journal of Laws of 2011, No. 122, item 696, as amended),ART 107m(1) and Act of 27 August 2004 on health care services financed from public funds (Journal of Laws of 2004, No. 210, item 2135, as amended), Regulation EC No 726/2004 (REG) Art 28b and Act of 5 December 1996 on the professions of doctor and dentist (Journal of Laws of 1997, No. 28, item 152, as amended), and the Medical Code of Ethics of January 2, 2004.

3. As mentioned by the authors in the INTRODUCTION, the use of ICS in COPD patients is indicated for use in patients with moderate to very severe COPD with repeated exacerbations according to the GOLD guidelines. In Table 1, GOLD A & B account for a much larger number than GOLD C & D in both groups (“newly diagnosed” and “switched”). This needs confirmation and explanation.

Ad 3. It is true. Unfortunately, the compliance of doctors with the recommendations is far from expected. This issue was risen in the discussion section: ‘Our finding supports previous evidence that ICS-containing DPI therapy is prescribed for patients across all GOLD classes in real-life settings [9]. Such overuse of ICS-containing therapy may expose to unnecessary risk of pneumonia. Older age (>65 years old), low FEV1 (< 50% of the predicted value), higher dose and long-time ICS use were identified as the risk factors in one of the most recent meta-analyses [10].’

The data set generated in our study precludes the explanation of factors affecting doctors’ decisions.

4. Patients enrolled in this study were evaluated by visiting the hospital 3 consecutive appointments, approximated 6 weeks apart (in the METHODS section). However, the period of Salflumix Easyhaler^®use during the study period was analyzed as 86±30 days. Table 1 shows that 90.5% of all patients used Salflumix Easyhaler^®for 2-4 weeks. It seems too short compared to what was mentioned in the METHODS section.

 Ad 4. The use of Salflumix Esyhaller for 2 – 8 weeks was the inclusion criterion in our study. We expected the follow-up period – the interval between the initial and the second follow-up visit of approximately 12 weeks (84 days). There was not much difference between the planned (84 days) and obtained period of observation (86 +/- 30 days) of exposure to Salflumix Esyhaller. The analysed period does not include the period of Salflumix Esyhaller before the initial visit.

5. Since the study period was very short, it would be considered very difficult to confirm the frequency of exacerbations during this period. However, the authors calculated the frequency (43.3%) of exacerbations over 86±30 days with the frequency (67.7%) of exacerbations over the past 12 months. I wonder how it was converted and if it is possible.

 Ad 5. The conversion was done by the proportion (multiplication by 365/86 = 4.24). We agree that such a calculation is burdened with a large error. We add such a sentence to the result section. ‘From the first to the third visit any exacerbation was reported in 45 patients (10.2%) – allowing for a rough estimation of exacerbation rate during 12 months at 43.2% (by multiply-ing by factor 4.24 obtained by dividing 365 days by 86).’

<Minor Comments>

Line 47: … Salflumix Easyhaler^® (Orion Pharma),… à (Orion Pharma, Warsaw, Poland)

Corrected – (Orion Pharma, Espoo, Finland).

Line 68: [for review 7] à [7]

Corrected

Line 77: Salflumix Easyhaler^® (Orion Pharma, Warsaw, Poland) à Salflumix Easyhaler^®

Corrected

Line 82: This IIS study à This IIS

Corrected

Line 108: good very good. à good, and very good.

Corrected

Line 117, 120: pts à points

Corrected

Line 168, 173: (p<0.001 for trend) à (p<0.001)

Corrected

Line 171, 173, 180: - Table 2 à (Table 2)

Corrected

Line 278-279: ‘I do not have any COI with the mentioned company, but it would be better to delete this mentioned part.’

As suggested

Reviewer 2 Report

1. If the sample size is 440, how the sample size was calculated? What were the inclusion and exclusion criteria of the trial?

2. Was volunteers trained before inhaling DPI through a spacer?

3. What was the significance of using Salflumix Easyhaler®DPI instead of its MDI?

4. Was there any side effect reported?

5. How the data was reported? Whether used a spirometer or peak flow meter or other digital methods?

6. Conclusion should give the actual finding with the future suggestion. Kindly elaborate.

Author Response

1. If the sample size is 440, how the sample size was calculated? What were the inclusion and exclusion criteria of the trial?

Ad 1. The size of the study group was not supported by statistical power analysis. The study planned to include 250 pulmonologists, but 220 were recreated and enrolled up to 2500 patients with asthma or COPD that fulfil the criteria within a period of 12 months. Mostly patients suffering for asthma (2.037) were recruited (this results were already published - Doniec Z, Olszanecka-Glinianowicz M, Hantulik P, Almgren-Rachtan A, Chudek J. The assessment of effectiveness, tolerance, and patient satisfaction with the use of a new fixed-dose combination product, containing salmeterol and fluticasone propionate, Salflumix Easyhaler^® in the treatment of asthma in the daily clinical practice. J Asthma. 2022 Jun 30:1-7. doi: 10.1080/02770903.2022.2093220.

We found that the subgroup of COPD patients (not included in the previous publication) of interest.

The inclusion criteria were presented in the Material & methods section: ‘The inclusion criteria for COPD patients were: adult patient with COPD and recently initiated (from 2 to 8 weeks) therapy with Salflumix Easyhaler® as a first fixed-dose DPI.’

2. Was volunteers trained before inhaling DPI through a spacer?

Ad 2. The role of the physician was to instruct the patient on how to use the DPI. The use of a spacer is recommended for MDI.

We add such a sentence: During the initial visit, patients were reinstructed with the appropriate application of Salflumix Easyhaler^®, and the patient information leaflet was used to address reported difficulties with the usage of the DPI.

3. What was the significance of using Salflumix Easyhaler^®DPI instead of its MDI?

Ad 3. Contrary metered dose inhalers (MDIs) are considered less dependent on a patient’s ability to produce airflow than DPIs are, but patients may have difficulties in coordinating device activation and inhalation, which can be overcome with the use of a spacer (a valved holding chamber) [8]. Of note, hydrofluorocarbons (HFCs) as MDIs propellants are greenhouse gases with a high global warming potential [9]. Therefore MDIs use has environmental consequences.

8. Vincken W, Levy ML, Scullion J, Usmani OS, Dekhuijzen PNR, Corrigan CJ. Spacer devices for inhaled therapy: why use them, and how? ERJ Open Res. 2018 Jun 18;4(2):00065-2018. doi: 10.1183/23120541.00065-2018. 
9. Janson C, Henderson R, Löfdahl M, Hedberg M, Sharma R, Wilkinson AJK. Carbon footprint impact of the choice of inhalers for asthma and COPD. Thorax. 2020;75(1):82-84. doi: 10.1136/thoraxjnl-2019-213744.
10. Was there any side effect reported?

Ad 4. Only 1 AEs of throat irritation, assessed as related to the use of the evaluated DPI was reported. Two patients discontinued the treatment, one due to the occurrence of AEs and the second due to clinical improvement with no feeling of the need for therapy continuation.

These sentences are a part of the manuscript.

5. How the data was reported? Whether used a spirometer or peak flow meter or other digital methods?

Ad 5. As stated ‘The project was supported by an Observational Card.’  Data from Observational Cards were entered into the database. The performer spirometry measurements across the study period were collected. Unfortunately due to the low number of spirometry, we decided not to present the data.

The information about monitoring was included as a limitation:’ The lack of FEV1 tracking by spirometry and a short period of Salflumix Easyhaler^® use should be mentioned as the main study limitations for the assessment of the efficacy. The study questionnaire included the possibility to enter FEV1 measures during all 3 visits, however, less than 20% of patients had more than one measurement precluding the performance of the analysis in everyday clinical practice. The GOLD guidelines recommend spirometry reassessment not less than once a year during the follow-up of COPD patients, but the COVID-19 pandemic could cause an even lower frequency of assessments.’.

6. Conclusion should give the actual finding with the future suggestion. Kindly elaborate.

Ad 6. We have modified the conclusion: ‘This study supports effectiveness, satisfaction and convenience with the use of this new product in COPD, and shows that ICS-containing DPI therapy is still improperly prescribed for patients with a low risk of COPD exacerbation in real-life settings.’

Round 2

Reviewer 1 Report

The authors gave clear, point-by-point answers to requests for revision and review.