A Study to Assess the Efficacy and Safety of Budesonide/Albuterol Metered-dose Inhaler (BDA MDI/PT027) in Adults and Children 4 Years of Age or Older With Asthma

Asthma Clinical Trial

— MANDALA  

Official title:

A Long-term, Randomized, Double-blind, Multicenter, Parallel-group, Phase III Study Evaluating the Efficacy and Safety of PT027 Compared to PT007 Administered as Needed in Response to Symptoms in Symptomatic Adults and Children 4 Years of Age or Older With Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03769090
• Other study ID #: AV003
• Status: Completed
• Phase: Phase 3
• Start date: December 13, 2018
• Est. completion date: February 7, 2022

Study information

• Verified date: September 2022
• Source: Bond Avillion 2 Development LP
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a randomized, double-blind, multicenter, parallel-group, variable-length study to compare 2 doses of BDA MDI (PT027) with AS MDI (PT007) on the time to first severe asthma exacerbation in adult, adolescent, and pediatric subjects with moderate to severe asthma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 3132
• Est. completion date: February 7, 2022
• Est. primary completion date: August 19, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 4 Years and older

Eligibility

Inclusion Criteria:

1. Female or male aged =4 years at the time of informed consent

2. Physician diagnosis of asthma documented for at least 1 year

3. Receiving 1 of the following scheduled asthma maintenance therapies for 3 months with

stable dosing for at least the last 4 weeks before Visit 1:

• Medium-to-high-dose inhaled corticosteroid (ICS)
• Medium-to-high-dose ICS and 1 additional maintenance therapy from the following:

leukotriene receptor antagonists (LTRA), long-acting muscarinic antagonists (LAMA), or theophylline

• Low-to-high-dose ICS in combination with long-acting ß2-adrenoreceptor agonist (LABA) with or without one additional maintenance therapy from the following: LTRA, LAMA, or theophylline

4. Prebronchodilator forced expiratory volume in 1 second (FEV1) of =40 to <90% predicted normal value for adults and adolescents, and =60 to <100% predicted normal value for subjects aged 4 to 11 years after withholding specified medications including short/rapid-acting ß2-adrenoreceptor agonist (SABA)

5. Demonstrate reversibility at Visit 1, with an increase in FEV1 =12% (and =200 mL for subjects aged =18 years) relative to baseline after administration of sponsor provided Ventolin via central spirometry. One re-test for reversibility testing is allowed within the screening period in advance of Visit 2

6. Demonstrate acceptable spirometry performance (i.e., meet American Thoracic Society/European Respiratory Society acceptability/repeatability criteria)

7. A documented history of at least 1 severe asthma exacerbation within 12 months before Visit 1

8. Able to perform acceptable and reproducible peak expiratory flow (PEF) measurements as assessed by the investigator

Exclusion Criteria:

1. Chronic obstructive pulmonary disease or other significant lung disease (e.g., chronic bronchitis, emphysema, bronchiectasis with the need of treatment, cystic fibrosis, or bronchopulmonary dysplasia)

2. Oral corticosteroid/SCS use (any dose and any indication) within 6 weeks before Visit 1

3. Chronic use of oral corticosteroids (OCS, =3 weeks use in 3 months prior to Visit 1)

4. Having received any marketed (e.g., omalizumab, mepolizumab, reslizumab, benralizumab) or investigational biologic within 3 months or any other prohibited medication

5. Current smokers, former smokers with >10 pack-years history, or former smokers who stopped smoking <6 months before Visit 1 (including all forms of tobacco, e-cigarettes [vaping], and marijuana)

6. Life-threatening asthma defined as any history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s) within 5 years of Visit 1

7. Historical or current evidence of a clinically significant disease

8. Cancer not in complete remission for at least 5 years

9. Hospitalization for psychiatric disorder or attempted suicide within 1 year of Visit 1

10. History of psychiatric disease, intellectual deficiency, poor motivation, or other conditions if their magnitude is limiting informed consent validity

11. Significant abuse of alcohol or drugs

Related Conditions & MeSH terms

• Asthma

Intervention

Combination Product:
• Budesonide/albuterol sulfate metered-dose inhaler 160/180 µg
Budesonide/albuterol sulfate combination inhalation aerosol
• Budesonide/albuterol sulfate metered-dose inhaler 80/180 µg
Budesonide/albuterol sulfate combination inhalation aerosol

Drug:
• Albuterol sulfate metered-dose inhaler 180 µg
Albuterol sulfate inhalation aerosol

Locations

Country	Name	City	State
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Buenos Aires
Argentina	Research Site	Córdoba
Argentina	Research Site	Florencio Varela
Argentina	Research Site	Lanús
Argentina	Research Site	Mar Del Plata
Argentina	Research Site	Mendoza
Argentina	Research Site	Mendoza
Argentina	Research Site	Quilmes
Argentina	Research Site	Rosario
Argentina	Research Site	Rosario
Argentina	Research Site	Rosario
Argentina	Research Site	Salta
Argentina	Research Site	San Fernando
Argentina	Research Site	San Miguel De Tucumán
Argentina	Research Site	San Miguel De Tucumán
Argentina	Research Site	San Miguel De Tucumán
Argentina	Research Site	Santa Fe
Argentina	Research Site	Santa Fe
Canada	Research Site	Ajax	Ontario
Canada	Research Site	Burlington	Ontario
Canada	Research Site	London	Ontario
Canada	Research Site	Newmarket	Ontario
Canada	Research Site	Québec	Quebec
Canada	Research Site	Sudbury	Ontario
Canada	Research Site	Toronto	Ontario
Canada	Research Site	Vancouver	British Columbia
Canada	Research Site	Waterloo	Ontario
Canada	Research Site	Windsor	Ontario
Czechia	Research Site	Beroun
Czechia	Research Site	Brandýs Nad Labem
Czechia	Research Site	Jindrichuv Hradec
Czechia	Research Site	Kralupy Nad Vltavou
Czechia	Research Site	Kurim
Czechia	Research Site	Lovosice
Czechia	Research Site	Miroslav
Czechia	Research Site	Neratovice
Czechia	Research Site	Praha
Czechia	Research Site	Praha
Czechia	Research Site	Rokycany
Czechia	Research Site	Tábor
Czechia	Research Site	Teplice
Czechia	Research Site	Varnsdorf
Germany	Research Site	Augsburg
Germany	Research Site	Bad Wörishofen
Germany	Research Site	Bamberg
Germany	Research Site	Bergisch Gladbach
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Berlin
Germany	Research Site	Bonn
Germany	Research Site	Cottbus
Germany	Research Site	Darmstadt
Germany	Research Site	Delitzsch
Germany	Research Site	Dortmund
Germany	Research Site	Essen
Germany	Research Site	Frankfurt
Germany	Research Site	Frankfurt
Germany	Research Site	Geesthacht
Germany	Research Site	Gelsenkirchen
Germany	Research Site	Halle
Germany	Research Site	Hamburg
Germany	Research Site	Hamburg
Germany	Research Site	Hannover
Germany	Research Site	Hannover
Germany	Research Site	Homburg
Germany	Research Site	Jena
Germany	Research Site	Köln
Germany	Research Site	Leipzig
Germany	Research Site	Leipzig
Germany	Research Site	Leipzig
Germany	Research Site	Leipzig
Germany	Research Site	Leipzig
Germany	Research Site	Lübeck
Germany	Research Site	Lübeck
Germany	Research Site	Magdeburg
Germany	Research Site	Marburg
Germany	Research Site	München
Germany	Research Site	München
Germany	Research Site	Neu Isenburg
Germany	Research Site	Peine
Germany	Research Site	Potsdam
Germany	Research Site	Radebeul
Germany	Research Site	Reinfeld
Germany	Research Site	Rosenheim
Germany	Research Site	Schleswig
Germany	Research Site	Wiesbaden
Germany	Research Site	Witten
Serbia	Research Site	Belgrade
Serbia	Research Site	Kragujevac
Serbia	Research Site	Niš
Serbia	Research Site	Sremska Kamenica
Serbia	Research Site	Valjevo
Slovakia	Research Site	Žilina
Slovakia	Research Site	Bratislava
Slovakia	Research Site	Ilava
Slovakia	Research Site	Kezmarok
Slovakia	Research Site	Košice
Slovakia	Research Site	Košice
Slovakia	Research Site	Poprad
Slovakia	Research Site	Prešov
South Africa	Research Site	Athlone
South Africa	Research Site	Bellville
South Africa	Research Site	Benoni
South Africa	Research Site	Bloemfontein
South Africa	Research Site	Boksburg
South Africa	Research Site	Cape Town
South Africa	Research Site	Cape Town
South Africa	Research Site	Durban
South Africa	Research Site	Durban
South Africa	Research Site	Gatesville
South Africa	Research Site	Johannesburg
South Africa	Research Site	Kempton Park
South Africa	Research Site	Kraaifontein
South Africa	Research Site	Middelburg
South Africa	Research Site	Mowbray
South Africa	Research Site	Newtown
South Africa	Research Site	Parktown
South Africa	Research Site	Pretoria
South Africa	Research Site	Pretoria
South Africa	Research Site	Roodepoort
South Africa	Research Site	Umhlanga
South Africa	Research Site	Umkomaas
South Africa	Research Site	Witbank
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Barcelona
Spain	Research Site	Girona
Spain	Research Site	Madrid
Spain	Research Site	Mérida
Spain	Research Site	Valencia
Ukraine	Research Site	Cherkasy
Ukraine	Research Site	Dnipro
Ukraine	Research Site	Ivano-Frankivs'k
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kharkiv
Ukraine	Research Site	Kherson
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Kyiv
Ukraine	Research Site	Luts'k
Ukraine	Research Site	Úzhgorod
Ukraine	Research Site	Vinnytsia
Ukraine	Research Site	Zaporizhzhya
Ukraine	Research Site	Zaporizhzhya
Ukraine	Research Site	Zaporizhzhya
United Kingdom	Research Site	Belfast
United Kingdom	Research Site	Blackpool
United Kingdom	Research Site	Bradford
United Kingdom	Research Site	Chippenham
United Kingdom	Research Site	Corby
United Kingdom	Research Site	Corby
United Kingdom	Research Site	Kenilworth
United Kingdom	Research Site	Liverpool
United Kingdom	Research Site	London
United Kingdom	Research Site	Newcastle Upon Tyne
United Kingdom	Research Site	Northwood
United Kingdom	Research Site	Nottingham
United Kingdom	Research Site	Peterborough
United Kingdom	Research Site	Romford
United Kingdom	Research Site	Shipley
United Kingdom	Research Site	Sidcup
United Kingdom	Research Site	Wokingham
United States	Research Site	Albany	Georgia
United States	Research Site	Albuquerque	New Mexico
United States	Research Site	Anderson	South Carolina
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Ann Arbor	Michigan
United States	Research Site	Asheville	North Carolina
United States	Research Site	Aurora	Colorado
United States	Research Site	Austin	Texas
United States	Research Site	Austin	Texas
United States	Research Site	Aventura	Florida
United States	Research Site	Bakersfield	California
United States	Research Site	Baltimore	Maryland
United States	Research Site	Bangor	Maine
United States	Research Site	Beaumont	Texas
United States	Research Site	Bellevue	Nebraska
United States	Research Site	Bellevue	Nebraska
United States	Research Site	Bellflower	California
United States	Research Site	Birmingham	Alabama
United States	Research Site	Blue Bell	Pennsylvania
United States	Research Site	Boerne	Texas
United States	Research Site	Boston	Massachusetts
United States	Research Site	Boynton Beach	Florida
United States	Research Site	Brick	New Jersey
United States	Research Site	Bronx	New York
United States	Research Site	Brooklyn	New York
United States	Research Site	Canoga Park	California
United States	Research Site	Cape Coral	Florida
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Charlotte	North Carolina
United States	Research Site	Chevy Chase	Maryland
United States	Research Site	Chicago	Illinois
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Cincinnati	Ohio
United States	Research Site	Clearwater	Florida
United States	Research Site	Clearwater	Florida
United States	Research Site	Clinton	South Carolina
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Colorado Springs	Colorado
United States	Research Site	Columbia	South Carolina
United States	Research Site	Columbus	Ohio
United States	Research Site	Conroe	Texas
United States	Research Site	Corsicana	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Dallas	Texas
United States	Research Site	Dayton	Ohio
United States	Research Site	Dayton	Ohio
United States	Research Site	DeLand	Florida
United States	Research Site	Denver	Colorado
United States	Research Site	Denver	Colorado
United States	Research Site	Denver	Colorado
United States	Research Site	Dublin	Ohio
United States	Research Site	East Providence	Rhode Island
United States	Research Site	Edmond	Oklahoma
United States	Research Site	El Paso	Texas
United States	Research Site	Encinitas	California
United States	Research Site	Erie	Pennsylvania
United States	Research Site	Fall River	Massachusetts
United States	Research Site	Fargo	North Dakota
United States	Research Site	Farmington Hills	Michigan
United States	Research Site	Flint	Michigan
United States	Research Site	Flint	Michigan
United States	Research Site	Gaffney	South Carolina
United States	Research Site	Gainesville	Florida
United States	Research Site	Galveston	Texas
United States	Research Site	Gastonia	North Carolina
United States	Research Site	Glendale	Arizona
United States	Research Site	Greenacres City	Florida
United States	Research Site	Greenfield	Wisconsin
United States	Research Site	Greenville	South Carolina
United States	Research Site	Hamtramck	Michigan
United States	Research Site	Hawthorne	California
United States	Research Site	Hazelwood	Missouri
United States	Research Site	Hialeah	Florida
United States	Research Site	High Point	North Carolina
United States	Research Site	Houston	Texas
United States	Research Site	Huntsville	Alabama
United States	Research Site	Iowa City	Iowa
United States	Research Site	Kerrville	Texas
United States	Research Site	Kissimmee	Florida
United States	Research Site	Las Vegas	Nevada
United States	Research Site	Lincoln	Nebraska
United States	Research Site	Little Rock	Arkansas
United States	Research Site	Live Oak	Texas
United States	Research Site	Long Beach	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Los Angeles	California
United States	Research Site	Marlton	New Jersey
United States	Research Site	Mayfield Heights	Ohio
United States	Research Site	McKinney	Texas
United States	Research Site	Medford	Oregon
United States	Research Site	Meridian	Idaho
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Miami	Florida
United States	Research Site	Mobile	Alabama
United States	Research Site	Monroe	North Carolina
United States	Research Site	Montgomery	Alabama
United States	Research Site	Morgantown	West Virginia
United States	Research Site	Mount Pleasant	South Carolina
United States	Research Site	Murray	Utah
United States	Research Site	Myrtle Beach	South Carolina
United States	Research Site	New Brunswick	New Jersey
United States	Research Site	New Hyde Park	New York
United States	Research Site	Newport Beach	California
United States	Research Site	Normal	Illinois
United States	Research Site	North Charleston	South Carolina
United States	Research Site	North Dartmouth	Massachusetts
United States	Research Site	Oklahoma City	Oklahoma
United States	Research Site	Orlando	Florida
United States	Research Site	Orlando	Florida
United States	Research Site	Overland Park	Kansas
United States	Research Site	Oviedo	Florida
United States	Research Site	Owensboro	Kentucky
United States	Research Site	Palmetto Bay	Florida
United States	Research Site	Panama City	Florida
United States	Research Site	Pearland	Texas
United States	Research Site	Pelzer	South Carolina
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Pembroke Pines	Florida
United States	Research Site	Peoria	Arizona
United States	Research Site	Philadelphia	Pennsylvania
United States	Research Site	Pittsburgh	Pennsylvania
United States	Research Site	Potsdam	New York
United States	Research Site	Providence	Rhode Island
United States	Research Site	Raleigh	North Carolina
United States	Research Site	Rancho Cucamonga	California
United States	Research Site	Redwood City	California
United States	Research Site	Rochester	Michigan
United States	Research Site	Rochester Hills	Michigan
United States	Research Site	Rock Hill	South Carolina
United States	Research Site	Sacramento	California
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Louis	Missouri
United States	Research Site	Saint Petersburg	Florida
United States	Research Site	Saint Petersburg	Florida
United States	Research Site	Salt Lake City	Utah
United States	Research Site	San Antonio	Texas
United States	Research Site	San Antonio	Texas
United States	Research Site	San Diego	California
United States	Research Site	San Francisco	California
United States	Research Site	San Jose	California
United States	Research Site	Scottsboro	Alabama
United States	Research Site	Scottsdale	Arizona
United States	Research Site	Sheffield	Alabama
United States	Research Site	Sherman	Texas
United States	Research Site	South Burlington	Vermont
United States	Research Site	Spartanburg	South Carolina
United States	Research Site	The Woodlands	Texas
United States	Research Site	Tomball	Texas
United States	Research Site	Toms River	New Jersey
United States	Research Site	Topeka	Kansas
United States	Research Site	Tulsa	Oklahoma
United States	Research Site	Tuscumbia	Alabama
United States	Research Site	Waco	Texas
United States	Research Site	Warwick	Rhode Island
United States	Research Site	Waterbury	Connecticut
United States	Research Site	Waxahachie	Texas
United States	Research Site	Westminster	California
United States	Research Site	White Marsh	Maryland
United States	Research Site	Winder	Georgia
United States	Research Site	Winston-Salem	North Carolina
United States	Research Site	Ypsilanti	Michigan

Sponsors (1)

Lead Sponsor	Collaborator
Bond Avillion 2 Development LP

Countries where clinical trial is conducted

United States,  Argentina,  Canada,  Czechia,  Germany,  Serbia,  Slovakia,  South Africa,  Spain,  Ukraine,  United Kingdom, 

References & Publications (2)

Chipps BE, Albers FC, Reilly L, Johnsson E, Cappelletti C, Papi A. Efficacy and safety of as-needed albuterol/budesonide versus albuterol in adults and children aged =4 years with moderate-to-severe asthma: rationale and design of the randomised, double-blind, active-controlled MANDALA study. BMJ Open Respir Res. 2021 Dec;8(1). pii: e001077. doi: 10.1136/bmjresp-2021-001077. — View Citation

Papi A, Chipps BE, Beasley R, Panettieri RA Jr, Israel E, Cooper M, Dunsire L, Jeynes-Ellis A, Johnsson E, Rees R, Cappelletti C, Albers FC. Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma. N Engl J Med. 2022 Jun 2;386(22):2071-2083. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With a Severe Asthma Exacerbation Event	Time to first severe asthma exacerbation will be calculated as the time from randomization until the start date of the first severe asthma exacerbation. An asthma exacerbation will be considered severe if it results in at least one of the following: a temporary bolus/burst of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening (a single depo-injectable dose of corticosteroids will be considered equivalent), an emergency room or urgent care visit (<24 hours in the facility for evaluation and treatment) due to asthma that required systemic corticosteroids, or an in-patient hospitalization (admission to an in-patient facility and/or = 24 hours in a healthcare facility) due to asthma. The descriptive summary shows the number of participants with a severe exacerbation event, occurring between the date of randomization up to the date of randomized treatment discontinuation or a change in maintenance therapy.	From randomization up to a discontinuation of randomized treatment or a change in maintenance therapy. The mean and median reporting period for all participants was 44 and 48 weeks, respectively.
Secondary	Annualized Severe Exacerbation Rate	The annualized severe exacerbation rate (severe exacerbations per year) is estimated from a negative binomial model with treatment, age group, region, and number of severe exacerbations in the last 12 months prior to randomization as categorical covariates. The logarithm of the time at risk is included as an offset variable.	From randomization up to discontinuation of randomized treatment or a change in maintenance therapy. The mean and median reporting period for all participants was 44 and 48 weeks, respectively.
Secondary	Total Annualized Dose of Systemic Corticosteroid (SCS)	This endpoint includes all systemic corticosteroids (SCS) taken in response to a severe exacerbation event from randomization up to randomized treatment discontinuation or a change in maintenance therapy. All SCS are standardized to equipotent doses of prednisone before deriving the total dose. The total annualized dose is calculated as the total dose of SCS divided by the duration of the randomized treatment period.	From randomization up to discontinuation of randomized treatment or a change in maintenance therapy. The mean and median reporting period for all participants was 44 and 48 weeks, respectively.
Secondary	Asthma Control Questionnaire-5 (ACQ-5) - Number of Participants Who Were Responders at Week 24	The ACQ-5 consists of 5 questions on symptom control, with each scored on a 7-point scale (0 = excellent asthma control; 6 = extremely poor control). The overall score (0 = excellent asthma control; 6 = extremely poor control, so a lower score is the better outcome) is the mean of the 5 symptom items. A responder is defined as a participant with a decrease from baseline to Week 24 overall ACQ-5 score of 0.5 or more. ACQ-5 is not validated for children less than 6 years old, data for participants who were 4 or 5 years old was excluded from the analysis of ACQ-5.	From baseline to Week 24
Secondary	Asthma Quality of Life Questionnaire for Participants Aged 12 Years and Older (AQLQ+12) - Number of Participants Who Were Responders at Week 24	The AQLQ+12 consists of 32 questions in 4 domains and is assessed on separate 7-point Likert scales from 1 to 7, with higher values indicating better health-related quality of life. The overall score is the mean of all responses. A responder is defined as a participant with an increase from baseline to week 24 AQLQ-12 score of at least 0.5.	From baseline to 24 weeks