A Study Testing the Superiority of CHF 1535 pMDI 800/24µg Total Daily Dose Compared to CHF 718 pMDI 800µg Total Daily Dose in Adults With Asthma on Medium or High-Dose Inhaled Corticosteroid

Asthma Clinical Trial

— FORCE2  

Official title:

A 12 Week, Randomized, Double-blind, Multicenter, Active Controlled, 2-Arm Parallel Group Study Testing the Superiority of CHF 1535 pMDI 800/24µg Total Daily Dose (Fixed Combination of Extrafine Beclomethasone Dipropionate Plus Formoterol Fumarate) Compared to CHF 718 pMDI 800µg Total Daily Dose (Extrafine Beclomethasone Dipropionate) in Adults With Asthma on Medium or High-Dose Inhaled Corticosteroid

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT05292586
• Other study ID #: CLI-05993AB8-02
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: October 5, 2022
• Est. completion date: June 2024

Study information

• Verified date: April 2024
• Source: Chiesi Farmaceutici S.p.A.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to compare the superiority of CHF 1535 compared to CHF 718 in subjects with asthma on medium or high dose inhaled corticosteroids.

Description:

This is a phase III, multicenter, randomized, double-blind active controlled 2-arm parallel group to compare superiority of CHF 1535 pMDI compared to CHF 718 pMDI in terms of change from baseline in FEV1 AUC0-12h at Week 12.

After screening, eligible subjects will enter a 2-week run-in period using CHF 718 (BDP) pMDI 100µg, followed by a 12-week double-blind, treatment period. Screened subjects who were on a medium dose ICS or medium dose ICS-LABA prior to the study will be put on CHF 718 pMDI 100µg 2 inhalations BID (TDD 400µg) during the 2-week run in period. Screened subjects who were on a high dose ICS prior to the study will be put on CHF 718 pMDI 100µg 4 inhalations BID (TDD 800µg) during the 2-week run in period.

Following the run-in period, eligible subjects will be randomized to one of two study drug arms (using a 1:1 allocation ratio) for 12 weeks. A total of 6 clinic visits (V0- V5) and a follow-up call (V6) will be performed during the study.

During the study, daily symptoms, rescue medication use and compliance with the study drug will be recorded via a subject electronic diary. Subject concomitant medications, and adverse events will be assessed and recorded throughout the study. At study visits, subjects will undergo vital signs, physical exam, 12-lead ECG, PEF, and spirometry measurements, including serial spirometry at V2 and V5. Symptoms will be assessed through disease specific questionnaires. Routine hematology, blood chemistry, and serum pregnancy testing will be performed before enrollment and at end of study.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 580
• Est. completion date: June 2024
• Est. primary completion date: June 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

1. Informed consent: A signed and dated written informed consent obtained prior to any study-related procedures.

2. Sex and age: Male or female aged =18 and =75 years.

3. Diagnosis of asthma: A documented history of asthma for at least 1 year, with onset before age 40

4. Stable asthma therapy: Use of medium-dose ICS with or without a LABA or high-dose ICS alone for 3 months (at a stable dose for at least 4 weeks prior to screening).

5. Lung function: Subjects with a pre-bronchodilator FEV1 =40% and =85% of predicted, after appropriate washout from bronchodilators, at the screening and randomization visits. In addition, the absolute value of the first pre-dose FEV1 at randomization (V2) must be at least 80% of the pre-bronchodilator value attained at screening.

6. Reversibility post-bronchodilator: Subjects with a positive reversibility to bronchodilator at screening, defined as an increase in FEV1 > 12% and > 200mL compared to baseline within 30 minutes after 4 inhalations of albuterol HFA pMDI 90µg/actuation.

Note for IC#5 and IC#6: In case the reversibility and/or quality threshold is not met at screening, the test can be performed once before randomization.

7. Female subjects:

a. WOCBP fulfilling one of the following criteria: i. WOCBP with fertile male partners: they and/or their partner must be willing to use a highly effective birth control method from the signing of the informed consent form and until the follow-up contact or ii. WOCBP with non-fertile male partners (contraception is not required in this case).

b. Female subjects of non-childbearing potential defined as physiologically incapable of becoming pregnant (i.e. post-menopausal or permanently sterile as per definitions given in Appendix 2). Tubal ligation or partial surgical interventions are not acceptable. If indicated, as per investigator's request, post-menopausal status may be confirmed by follicle-stimulating hormone levels (according to local laboratory ranges).

8. Cooperative attitude and ability to demonstrate correct use of the pMDI inhalers and eDiary/peak flow meter.

Exclusion Criteria:

1. Pregnancy or lactation: where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive pregnancy test (serum and urine pregnancy test to be performed at screening visit and urine pregnancy test to be performed prior to randomization).

2. Poor compliance with run-in medication or eDiary completion <50% before randomization.

3. History of "at risk" asthma: History of near-fatal asthma or of a past hospitalization for asthma in intensive care unit which, in the judgement of the investigator, may place the subject at undue risk.

4. Recent asthma exacerbation: Hospitalization, emergency room admission or use of systemic corticosteroids for an asthma exacerbation in the 4 weeks prior to screening visit or during the run-in period.

5. Unresolved respiratory tract infection (RTI) in the 4 weeks prior to the screening visit or during run-in period. Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 8 weeks or complications from this disease, which have not resolved within 14 days prior to screening.

6. Unstable ICS dose during the 4 weeks prior to screening visit, including any change in dose, schedule, or formulation.

7. Use of systemic corticosteroid medication in the 4 weeks prior to screening or slow-release corticosteroids in the 12 weeks before screening.

8. Respiratory disorders other than asthma: History of a diagnosis of cystic fibrosis, bronchiectasis, COPD (as defined by the current GOLD Report), alpha-1 antitrypsin deficiency, or any other significant lung disease which may interfere with study evaluations.

9. Smoking status: Current smokers or ex-smokers with total cumulative exposure equal to or more than 10 pack-years or having stopped smoking within one year prior to screening visit.

10. E-cigarette status: Current e-cigarettes users at the time of the screening visit.

11. Cannabis usage: Current use of inhaled or oral cannabis products (e.g. marijuana).

12. Substance abuse: Subjects with a history of alcohol or substance/drug abuse within 12 months prior to screening.

13. Cardiovascular diseases: Subjects who have clinically significant cardiovascular condition such as, but not limited to, unstable ischemic heart disease, NYHA Class III/IV heart failure, acute ischemic heart disease within one year prior to study entry, known history of atrial fibrillation or history of sustained and non-sustained cardiac arrhythmias diagnosed within the last 6 months prior to screening, not controlled with a rate control strategy. Note: Subjects with Permanent Atrial Fibrillation (for at least 6 months) with a resting ventricular rate <100/min, controlled with a rate control strategy (i.e., selective ß-blocker, calcium channel blocker, pacemaker placement, digoxin, or ablation therapy) can be considered for the enrollment.

14. ECG criteria: An abnormal and clinically significant 12-lead electrocardiogram (ECG) which may impact the safety of the subject according to Investigator's judgement. In terms of the QTcF, subjects with QTcF >450ms for males or QTcF >470ms for females at screening or at randomization visits (criterion not applicable for subject with pacemaker or permanent atrial fibrillation).

15. Other medical conditions: Other active severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.

16. Vaccination: Subjects having received a vaccination within 2 weeks prior to screening or during the run-in period.

17. Subjects' wellbeing: Subjects mentally or legally incapacitated, including but not limited to subjects who are institutionalized or incarcerated.

18. Hypersensitivity: Subjects with known intolerance, hypersensitivity or contraindication to treatment with ß2-agonists, ICS, or propellant gases/excipients.

19. Surgery: Subjects with major surgery in the 3 months prior to the screening visit or planned surgery during the study.

20. Additional treatment: Subjects treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing before the screening), non-selective beta-blocking drugs, quinidine, quinidine-like anti-arrhythmic, or any medication with a QTc prolongation potential or a history of QTc prolongation.

21. Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants.

22. Subjects with concomitant immunosuppressive therapy, use of oral or injected corticosteroids, anti-IgE, anti-IL5 or other monoclonal or polyclonal antibodies within 12 weeks prior to screening.

23. Subjects who are receiving any therapy that could interfere with the study drugs according to investigator's opinion.

24. Participating in other investigational trial: Subjects who have received an investigational drug within 1 month or 5 half-lives (whichever is greater) prior to screening visit, or have been previously randomized in this trial, or are currently participating in another clinical trial.

25. Spacer: The need to use a spacer for correct self-administration of a pMDI.

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Beclomethasone Dipropionate/Formoterol Fumarate
Available in pressurized inhalation solution BDP/FF 200/6 µg
• Beclomethasone Dipropionate
Available in pressurized inhalation solution BDP 100 µg

Locations

Country	Name	City	State
United States	Chiesi Clinical Trial Site 840871	Adairsville	Georgia
United States	Chiesi Clinical Trial Site 840851	Albuquerque	New Mexico
United States	Chiesi Clinical Trial Site 840892	Anderson	South Carolina
United States	Chiesi Clinical Trial Site 840815	Baytown	Texas
United States	Chiesi Clinical Trial Site 840867	Bellevue	Nebraska
United States	Chiesi Clinical Trial Site 840882	Bellingham	Washington
United States	Chiesi Clinical Trial Site 840874	Boerne	Texas
United States	Chiesi Clinical Trial Site 840836	Brick	New Jersey
United States	Chiesi Clinical Trial Site 840845	Carrollton	Texas
United States	Chiesi Clinical Trial Site 840895	Chandler	Arizona
United States	Chiesi Clinical Trial Site 840873	Colorado Springs	Colorado
United States	Chiesi Clinical Trial Site 840844	Columbia	South Carolina
United States	Chiesi Clinical Trial Site 840859	Columbia	Missouri
United States	Chiesi Clinical Trial Site 840820	Coral Gables	Florida
United States	Chiesi Clinical Trial Site 840841	Cutler Bay	Florida
United States	Chiesi Clinical Trial Site 840876	Dallas	Texas
United States	Chiesi Clinical Trial Site 840800	Denver	Colorado
United States	Chiesi Clinical Trial Site 840866	Edmond	Oklahoma
United States	Chiesi Clinical Trial Site 840803	El Paso	Texas
United States	Chiesi Clinical Trial Site 840856	Encinitas	California
United States	Chiesi Clinical Trial Site 840884	Grants Pass	Oregon
United States	Chiesi Clinical Trial Site 840817	Greenacres City	Florida
United States	Chiesi Clinical Trial Site 840870	Greenfield	Wisconsin
United States	Chiesi Clinical Trial Site 840850	Greenville	South Carolina
United States	Chiesi Clinical Trial Site 840897	Henderson	Nevada
United States	Chiesi Clinical Trial Site 840822	Hialeah	Florida
United States	Chiesi Clinical Trial Site 840838	Hialeah	Florida
United States	Chiesi Clinical Trial Site 840833	Houston	Texas
United States	Chiesi Clinical Trial Site 840843	Huntington Beach	California
United States	Chiesi Clinical Trial Site 840860	Huntington Beach	California
United States	Chiesi Clinical Trial Site 840864	Kissimmee	Florida
United States	Chiesi Clinical Trial Site 840812	Knoxville	Tennessee
United States	Chiesi Clinical Trial Site 840896	Long Beach	California
United States	Chiesi Clinical Trial Site 840810	Los Angeles	California
United States	Chiesi Clinical Trial Site 840883	Los Angeles	California
United States	Chiesi Clinical Trial Site 840816	McKinney	Texas
United States	Chiesi Clinical Trial Site 840862	McKinney	Texas
United States	Chiesi Clinical Trial Site 840830	Medford	Oregon
United States	Chiesi Clinical Trial Site 840802	Miami	Florida
United States	Chiesi Clinical Trial Site 840806	Miami	Florida
United States	Chiesi Clinical Trial Site 840814	Miami	Florida
United States	Chiesi Clinical Trial Site 840818	Miami	Florida
United States	Chiesi Clinical Trial Site 840819	Miami	Florida
United States	Chiesi Clinical Trial Site 840821	Miami	Florida
United States	Chiesi Clinical Trial Site 840828	Miami	Florida
United States	Chiesi Clinical Trial Site 840829	Miami	Florida
United States	Chiesi Clinical Trial Site 840835	Miami	Florida
United States	Chiesi Clinical Trial Site 840847	Miami	Florida
United States	Chiesi Clinical Trial Site 840855	Miami	Florida
United States	Chiesi Clinical Trial Site 840875	Miami	Florida
United States	Chiesi Clinical Trial Site 840887	Miami	Florida
United States	Chiesi Clinical Trial Site 840809	Miami Gardens	Florida
United States	Chiesi Clinical Trial Site 840863	Miami Lakes	Florida
United States	Chiesi Clinical Trial Site 840865	Miami Lakes	Florida
United States	Chiesi Clinical Trial Site 840831	Miami Springs	Florida
United States	Chiesi Clinical Trial Site 840858	Mobile	Alabama
United States	Chiesi Clinical Trial Site 840899	Monroe	North Carolina
United States	Chiesi Clinical Trial Site 840893	Murray	Utah
United States	Chiesi Clinical Trial Site 840869	Newport Beach	California
United States	Chiesi Clinical Trial Site 840826	North Dartmouth	Massachusetts
United States	Chiesi Clinical Trial Site 840890	North Hollywood	California
United States	Chiesi Clinical Trial Site 840872	North Las Vegas	Nevada
United States	Chiesi Clinical Trial Site 840808	Northridge	California
United States	Chiesi Clinical Trial Site 840839	Palmetto Bay	Florida
United States	Chiesi Clinical Trial Site 840827	Pembroke Pines	Florida
United States	Chiesi Clinical Trial Site 840840	Pembroke Pines	Florida
United States	Chiesi Clinical Trial Site 840879	Pomona	California
United States	Chiesi Clinical Trial Site 840811	Port Saint Lucie	Florida
United States	Chiesi Clinical Trial Site 840853	Portland	Oregon
United States	Chiesi Clinical Trial Site 840852	Raleigh	North Carolina
United States	Chiesi Clinical Trial Site 840837	Riverton	Utah
United States	Chiesi Clinical Trial Site 840894	Rock Hill	South Carolina
United States	Chiesi Clinical Trial Site 840868	Sacramento	California
United States	Chiesi Clinical Trial Site 840888	Saint Charles	Missouri
United States	Chiesi Clinical Trial Site 840846	Saint Louis	Missouri
United States	Chiesi Clinical Trial Site 840834	Saint Petersburg	Florida
United States	Chiesi Clinical Trial Site 840880	Saint Petersburg	Florida
United States	Chiesi Clinical Trial Site 840889	Saint Petersburg	Florida
United States	Chiesi Clinical Trial Site 840823	San Antonio	Texas
United States	Chiesi Clinical Trial Site 840842	San Antonio	Texas
United States	Chiesi Clinical Trial Site 840857	San Antonio	Texas
United States	Chiesi Clinical Trial Site 840849	San Diego	California
United States	Chiesi Clinical Trial Site 840877	San Diego	California
United States	Chiesi Clinical Trial Site 840861	San Jose	California
United States	Chiesi Clinical Trial Site 840891	Spartanburg	South Carolina
United States	Chiesi Clinical Trial Site 840801	Sugar Land	Texas
United States	Chiesi Clinical Trial Site 840807	Tallahassee	Florida
United States	Chiesi Clinical Trial Site 840878	Tulsa	Oklahoma
United States	Chiesi Clinical Trial Site 840885	Warwick	Rhode Island
United States	Chiesi Clinical Trial Site 840881	Westminster	California
United States	Chiesi Clinical Trial Site 840824	White Marsh	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
Chiesi Farmaceutici S.p.A.

Country where clinical trial is conducted

United States, 

References & Publications (32)

Averell CM, Laliberte F, Duh MS, Wu JW, Germain G, Faison S. Characterizing Real-World Use Of Tiotropium In Asthma In The USA. J Asthma Allergy. 2019 Oct 7;12:309-321. doi: 10.2147/JAA.S216932. eCollection 2019. — View Citation

Bateman ED, Boushey HA, Bousquet J, Busse WW, Clark TJ, Pauwels RA, Pedersen SE; GOAL Investigators Group. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med. 2004 Oct 15;170(8):836-44. doi: 10.1164/rccm.200401-033OC. Epub 2004 Jul 15. — View Citation

Chau-Etchepare F, Hoerger JL, Kuhn BT, Zeki AA, Haczku A, Louie S, Kenyon NJ, Davis CE, Schivo M. Viruses and non-allergen environmental triggers in asthma. J Investig Med. 2019 Oct;67(7):1029-1041. doi: 10.1136/jim-2019-001000. Epub 2019 Jul 27. — View Citation

Corradi M, Spinola M, Petruzzelli S, Kuna P. High-dose beclometasone dipropionate/formoterol fumarate in fixed-dose combination for the treatment of asthma. Ther Adv Respir Dis. 2016 Oct;10(5):492-502. doi: 10.1177/1753465816654442. Epub 2016 Jun 23. — View Citation

Davis J, Trudo F, Siddall J, Small M. Burden of asthma among patients adherent to ICS/LABA: A real-world study. J Asthma. 2019 Mar;56(3):332-340. doi: 10.1080/02770903.2018.1455858. Epub 2018 Apr 6. — View Citation

Ellepola AN, Samaranayake LP. Inhalational and topical steroids, and oral candidosis: a mini review. Oral Dis. 2001 Jul;7(4):211-6. — View Citation

Fagerland MW, Lydersen S, Laake P. Recommended confidence intervals for two independent binomial proportions. Stat Methods Med Res. 2015 Apr;24(2):224-54. doi: 10.1177/0962280211415469. Epub 2011 Oct 13. — View Citation

Fink JB, Colice GL, Hodder R. Inhaler devices for patients with COPD. COPD. 2013 Aug;10(4):523-35. doi: 10.3109/15412555.2012.761960. Epub 2013 Mar 28. — View Citation

Forno E, Celedon JC. Asthma and ethnic minorities: socioeconomic status and beyond. Curr Opin Allergy Clin Immunol. 2009 Apr;9(2):154-60. doi: 10.1097/aci.0b013e3283292207. — View Citation

GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222. doi: 10.1016/S0140-6736(20)30925-9. Erratum In: Lancet. 2020 Nov 14;396(10262):1562. — View Citation

Global Initiative for Asthma (GINA): global strategy for asthma management and prevention. 2021 update. (2021). Available from: www.ginasthma.org.

Graham BL, Steenbruggen I, Miller MR, Barjaktarevic IZ, Cooper BG, Hall GL, Hallstrand TS, Kaminsky DA, McCarthy K, McCormack MC, Oropez CE, Rosenfeld M, Stanojevic S, Swanney MP, Thompson BR. Standardization of Spirometry 2019 Update. An Official American Thoracic Society and European Respiratory Society Technical Statement. Am J Respir Crit Care Med. 2019 Oct 15;200(8):e70-e88. doi: 10.1164/rccm.201908-1590ST. — View Citation

Juniper EF, Bousquet J, Abetz L, Bateman ED; GOAL Committee. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med. 2006 Apr;100(4):616-21. doi: 10.1016/j.rmed.2005.08.012. Epub 2005 Oct 13. — View Citation

Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a questionnaire to measure asthma control. Eur Respir J. 1999 Oct;14(4):902-7. doi: 10.1034/j.1399-3003.1999.14d29.x. — View Citation

Kardas G, Kuna P, Panek M. Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling. Front Immunol. 2020 Jun 18;11:1134. doi: 10.3389/fimmu.2020.01134. eCollection 2020. — View Citation

Kerstjens HAM, Maspero J, Chapman KR, van Zyl-Smit RN, Hosoe M, Tanase AM, Lavecchia C, Pethe A, Shu X, D'Andrea P; IRIDIUM trial investigators. Once-daily, single-inhaler mometasone-indacaterol-glycopyrronium versus mometasone-indacaterol or twice-daily fluticasone-salmeterol in patients with inadequately controlled asthma (IRIDIUM): a randomised, double-blind, controlled phase 3 study. Lancet Respir Med. 2020 Oct;8(10):1000-1012. doi: 10.1016/S2213-2600(20)30190-9. Epub 2020 Jul 9. — View Citation

Kippelen P, Anderson SD, Hallstrand TS. Mechanisms and Biomarkers of Exercise-Induced Bronchoconstriction. Immunol Allergy Clin North Am. 2018 May;38(2):165-182. doi: 10.1016/j.iac.2018.01.008. — View Citation

Lee LA, Bailes Z, Barnes N, Boulet LP, Edwards D, Fowler A, Hanania NA, Kerstjens HAM, Kerwin E, Nathan R, Oppenheimer J, Papi A, Pascoe S, Brusselle G, Peachey G, Sule N, Tabberer M, Pavord ID. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet Respir Med. 2021 Jan;9(1):69-84. doi: 10.1016/S2213-2600(20)30389-1. Epub 2020 Sep 9. Erratum In: Lancet Respir Med. 2021 Jan 4;: — View Citation

Lee LK, Obi E, Paknis B, Kavati A, Chipps B. Asthma control and disease burden in patients with asthma and allergic comorbidities. J Asthma. 2018 Feb;55(2):208-219. doi: 10.1080/02770903.2017.1316394. Epub 2017 Jun 6. — View Citation

Lipworth B, Manoharan A, Anderson W. Unlocking the quiet zone: the small airway asthma phenotype. Lancet Respir Med. 2014 Jun;2(6):497-506. doi: 10.1016/S2213-2600(14)70103-1. — View Citation

Paggiaro P, Corradi M, Latorre M, Raptis H, Muraro A, Gessner C, Siergiejko Z, Scuri M, Petruzzelli S. High strength extrafine pMDI beclometasone/formoterol (200/6 mug) is effective in asthma patients not adequately controlled on medium-high dose of inhaled corticosteroids. BMC Pulm Med. 2016 Dec 9;16(1):180. doi: 10.1186/s12890-016-0335-9. — View Citation

Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM; ICAT SE study group. Beclomethasone/formoterol vs fluticasone/salmeterol inhaled combination in moderate to severe asthma. Allergy. 2007 Oct;62(10):1182-8. doi: 10.1111/j.1398-9995.2007.01493.x. — View Citation

Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM; Inhaled Combination Asthma Treatment versus SYmbicort (ICAT SY) Study Group. Beclomethasone/formoterol versus budesonide/formoterol combination therapy in asthma. Eur Respir J. 2007 Apr;29(4):682-9. doi: 10.1183/09031936.00095906. Epub 2006 Nov 15. Erratum In: Eur Respir J. 2007 Jun;29(6):1286. Eur Respir J. 2008 Sep;32(3):822. — View Citation

Pelaia C, Crimi C, Vatrella A, Tinello C, Terracciano R, Pelaia G. Molecular Targets for Biological Therapies of Severe Asthma. Front Immunol. 2020 Nov 30;11:603312. doi: 10.3389/fimmu.2020.603312. eCollection 2020. — View Citation

Quanjer PH, Stanojevic S, Cole TJ, Baur X, Hall GL, Culver BH, Enright PL, Hankinson JL, Ip MS, Zheng J, Stocks J; ERS Global Lung Function Initiative. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. Eur Respir J. 2012 Dec;40(6):1324-43. doi: 10.1183/09031936.00080312. Epub 2012 Jun 27. — View Citation

Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB, Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy ML, O'Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan SD, Szefler SJ, Thomas MD, Wenzel SE; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med. 2009 Jul 1;180(1):59-99. doi: 10.1164/rccm.200801-060ST. — View Citation

Roger JH, Bratton DJ, Mayer B, Abellan JJ, Keene ON. Treatment policy estimands for recurrent event data using data collected after cessation of randomised treatment. Pharm Stat. 2019 Jan;18(1):85-95. doi: 10.1002/pst.1910. Epub 2018 Nov 8. — View Citation

Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled corticosteroids: current understanding and review of the literature. Chest. 2004 Jul;126(1):213-9. doi: 10.1378/chest.126.1.213. — View Citation

Sobieraj DM, Baker WL, Nguyen E, Weeda ER, Coleman CI, White CM, Lazarus SC, Blake KV, Lang JE. Association of Inhaled Corticosteroids and Long-Acting Muscarinic Antagonists With Asthma Control in Patients With Uncontrolled, Persistent Asthma: A Systematic Review and Meta-analysis. JAMA. 2018 Apr 10;319(14):1473-1484. doi: 10.1001/jama.2018.2757. Erratum In: JAMA. 2018 May 8;319(18):1939. — View Citation

Virchow JC, Backer V, de Blay F, Kuna P, Ljorring C, Prieto JL, Villesen HH. Defining moderate asthma exacerbations in clinical trials based on ATS/ERS joint statement. Respir Med. 2015 May;109(5):547-56. doi: 10.1016/j.rmed.2015.01.012. Epub 2015 Feb 3. — View Citation

Virchow JC, Kuna P, Paggiaro P, Papi A, Singh D, Corre S, Zuccaro F, Vele A, Kots M, Georges G, Petruzzelli S, Canonica GW. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet. 2019 Nov 9;394(10210):1737-1749. doi: 10.1016/S0140-6736(19)32215-9. Epub 2019 Sep 30. — View Citation

Zein JG, Udeh BL, Teague WG, Koroukian SM, Schlitz NK, Bleecker ER, Busse WB, Calhoun WJ, Castro M, Comhair SA, Fitzpatrick AM, Israel E, Wenzel SE, Holguin F, Gaston BM, Erzurum SC; Severe Asthma Research Program. Impact of Age and Sex on Outcomes and Hospital Cost of Acute Asthma in the United States, 2011-2012. PLoS One. 2016 Jun 13;11(6):e0157301. doi: 10.1371/journal.pone.0157301. eCollection 2016. — View Citation

* Note: There are 32 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change from baseline in FEV1 Area Under the Curve from 0 to 12 hours post-dose (AUC0-12h) at Week 12 calculated as the difference of the values for CHF 1535 pMDI 800/24µg total daily dose (TDD) and CHF 718 pMDI 800µg TDD.		Week 12
Secondary	Change from baseline in peak FEV1 within the first 3 hours post-dose at Week 12 calculated as the difference of the values for CHF 1535 pMDI 800/24µg TDD and CHF 718 pMDI 800µg TDD.		Week 12