A 12-week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants With Inadequately Controlled Asthma (LITHOS) (LITHOS)

A Randomized, Double-Blind, Parallel Group, Multicenter 12 Week Study to Assess the Efficacy and Safety of Budesonide and Formoterol Fumarate Metered Dose Inhaler Relative to Budesonide Metered Dose Inhaler in Participants With Inadequately Controlled Asthma (LITHOS)

This is a 12-week study to evaluate the efficacy and safety of budesonide and formoterol fumarate metered dose inhaler relative to budesonide metered dose inhaler in adults and adolescents with inadequately controlled asthma.

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: BFF MDI 160/9.6 μg BID (320/19.2μg/day); Drug: BD MDI 160 μg BID (320 μg/day)

Detailed Description

This is a Phase III, randomized, double-blind, parallel group, multicenter study comparing Budesonide and Formoterol Fumarate Metered Dose Inhaler (BFF MDI) 160/9.6 μg twice daily (BID) to Budesonide MDI 160 μg (BD MDI), over 12 weeks. The study population will consist of adult and adolescent participants with asthma who remain inadequately controlled, as demonstrated by an Asthma Control Questionnaire (ACQ)-7 total score ≥1.5, despite treatment with low dose inhaled corticosteroid (ICS) or ICS/long-acting beta2-agonist (LABA). This study is to assess the benefits and safety of BFF MDI on lung function and asthma health-related quality of life.

This study will be conducted at approximately 90 sites worldwide and will randomize approximately 340 adult and adolescent participants.

• Study Type: Interventional
• Enrollment (Actual): 374
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • British Columbia
    • Kamloops, British Columbia, Canada, V2C 5T1
      • Research Site
    • Kelowna, British Columbia, Canada, V1Y 4N7
      • Research Site
    • Penticton, British Columbia, Canada, V2A 5L5
      • Research Site
  • Ontario
    • Ajax, Ontario, Canada, L1S 2J5
      • Research Site
    • Toronto, Ontario, Canada, M9V 4B4
      • Research Site
    • Winchester, Ontario, Canada, K0C 2K0
      • Research Site
    • Windsor, Ontario, Canada, N8X 2G1
      • Research Site
  • Quebec
    • Montreal, Quebec, Canada, H3M 1L3
      • Research Site
    • Québec, Quebec, Canada, G1G 3Y8
      • Research Site
    • Québec, Quebec, Canada, G1V 4W2
      • Research Site
• Czechia
  • Jindřichův Hradec, Czechia, 377 01
    • Research Site
  • Louny, Czechia, 44 001
    • Research Site
  • Lovosice, Czechia, 410 02
    • Research Site
  • Miroslav, Czechia, 671 72
    • Research Site
  • Prague, Czechia, 190 00
    • Research Site
  • Prague, Czechia, 148 00
    • Research Site
  • Teplice, Czechia, 415 01
    • Research Site
  • Varnsdorf, Czechia, 407 47
    • Research Site
• Malaysia
  • Alor Star, Malaysia, 5460
    • Research Site
  • George Town, Malaysia, 10450
    • Research Site
  • Ipoh, Malaysia, 30990
    • Research Site
  • Kajang, Malaysia, 43000
    • Research Site
  • Kota Bharu, Malaysia, 15586
    • Research Site
  • Kuala Lumpur, Malaysia, 59100
    • Research Site
  • Kuala Terengganu, Malaysia, 20400
    • Research Site
  • Sarawak Miri, Malaysia, 98000
    • Research Site
  • Seremban, Malaysia, 70300
    • Research Site
• Philippines
  • Iloilo City, Philippines, 5000
    • Research Site
  • Manila, Philippines, 1000
    • Research Site
  • Manila, Philippines, 1014
    • Research Site
  • Marilao, Philippines, 3019
    • Research Site
• South Africa
  • Durban, South Africa, 4001
    • Research Site
  • Durban, South Africa, 4450
    • Research Site
  • Newton, South Africa, 2113
    • Research Site
  • Pretoria, South Africa, 0186
    • Research Site
  • Tygervalley, South Africa, 7530
    • Research Site
• South Korea
  • Daegu, South Korea, 42415
    • Research Site
  • Guri-si, South Korea, 11923
    • Research Site
  • Jeonju, South Korea, 54907
    • Research Site
  • Seoul, South Korea, 03312
    • Research Site
  • Ulsan, South Korea, 44033
    • Research Site
• United States
  • Arizona
    • Chandler, Arizona, United States, 85224
      • Research Site
    • Mesa, Arizona, United States, 85213
      • Research Site
    • Tucson, Arizona, United States, 85745
      • Research Site
  • California
    • Bakersfield, California, United States, 93301
      • Research Site
    • Encinitas, California, United States, 92024
      • Research Site
    • Fresno, California, United States, 93720
      • Research Site
    • Huntington Beach, California, United States, 92647
      • Research Site
    • Los Angeles, California, United States, 90025
      • Research Site
    • Los Angeles, California, United States, 90017
      • Research Site
    • Los Angeles, California, United States, 90048
      • Research Site
    • Newport Beach, California, United States, 92663
      • Research Site
    • Northridge, California, United States, 91324
      • Research Site
    • Sacramento, California, United States, 95823
      • Research Site
    • San Diego, California, United States, 92123
      • Research Site
    • San Jose, California, United States, 95117
      • Research Site
    • Ventura, California, United States, 93003
      • Research Site
    • Walnut Creek, California, United States, 94598
      • Research Site
  • Florida
    • Cutler Bay, Florida, United States, 33189
      • Research Site
    • DeBary, Florida, United States, 32713
      • Research Site
    • DeLand, Florida, United States, 32720
      • Research Site
    • Miami, Florida, United States, 33173
      • Research Site
    • Miami, Florida, United States, 33175
      • Research Site
    • Miami, Florida, United States, 33155
      • Research Site
    • Miami, Florida, United States, 33180
      • Research Site
    • Plantation, Florida, United States, 33324
      • Research Site
    • Tampa, Florida, United States, 33607
      • Research Site
  • Georgia
    • Atlanta, Georgia, United States, 30361
      • Research Site
  • Indiana
    • South Bend, Indiana, United States, 46617
      • Research Site
  • Kentucky
    • Lexington, Kentucky, United States, 40509
      • Research Site
  • Maryland
    • Annapolis, Maryland, United States, 21401
      • Research Site
    • White Marsh, Maryland, United States, 21162
      • Research Site
  • Massachusetts
    • North Dartmouth, Massachusetts, United States, 02747
      • Research Site
  • Michigan
    • Farmington Hills, Michigan, United States, 48336
      • Research Site
  • Missouri
    • Rolla, Missouri, United States, 65401
      • Research Site
    • St Louis, Missouri, United States, 63141
      • Research Site
  • Montana
    • Kalispell, Montana, United States, 59901
      • Research Site
    • Missoula, Montana, United States, 59808
      • Research Site
  • Nebraska
    • Bellevue, Nebraska, United States, 68123
      • Research Site
  • Nevada
    • Henderson, Nevada, United States, 89052
      • Research Site
    • Las Vegas, Nevada, United States, 89102
      • Research Site
    • North Las Vegas, Nevada, United States, 89030
      • Research Site
  • New Hampshire
    • Portsmouth, New Hampshire, United States, 03801
      • Research Site
  • New York
    • New Windsor, New York, United States, 12553
      • Research Site
    • Schenectady, New York, United States, 12308
      • Research Site
  • North Carolina
    • Fayetteville, North Carolina, United States, 28314
      • Research Site
    • Raleigh, North Carolina, United States, 27607
      • Research Site
  • Ohio
    • Columbus, Ohio, United States, 43215
      • Research Site
  • Oklahoma
    • Edmond, Oklahoma, United States, 73034
      • Research Site
    • Oklahoma City, Oklahoma, United States, 73120
      • Research Site
  • Pennsylvania
    • Hatboro, Pennsylvania, United States, 19040
      • Research Site
    • Pittsburgh, Pennsylvania, United States, 15236
      • Research Site
  • Texas
    • Austin, Texas, United States, 78704
      • Research Site
    • Beaumont, Texas, United States, 77701
      • Research Site
    • Boerne, Texas, United States, 78006
      • Research Site
    • El Paso, Texas, United States, 79912
      • Research Site
    • Forney, Texas, United States, 75126
      • Research Site
    • San Antonio, Texas, United States, 78229
      • Research Site
    • San Antonio, Texas, United States, 78258
      • Research Site
    • Victoria, Texas, United States, 77901
      • Research Site
    • Waco, Texas, United States, 76712
      • Research Site
  • Utah
    • American Fork, Utah, United States, 84003
      • Research Site
    • Bountiful, Utah, United States, 84010
      • Research Site
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53228
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 80 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria

1. 12 to 80 years of age, male and female, BMI <40 kg/m2; females of childbearing potential should be using highly effective birth control.
2. Participants who have a documented history of physician-diagnosed asthma ≥ 6 months prior to Visit 1, according to GINA guidelines [GINA 2021]. Healthcare records for one year prior to Visit 1 must be provided for adolescent participants (12 to < 18 years of age) to ensure consistent evaluation and follow-up of treatment in those participants.
3. Participants who have been regularly using a stable daily ICS or an ICS/LABA regimen (including a stable ICS dose), with allowed ICS doses, for at least 8 weeks prior to Visit 1.
4. ACQ-7 total score ≥ 1.5 at Visits 1 and 4.
5. A pre-bronchodilator/pre-dose FEV1 < 90% predicted normal value at Visits 1, 2, and 3 and a pre-dose FEV1 of 50% to 90% at Visit 4 (pre-randomization).
6. Reversibility to albuterol, defined as a post-albuterol increase in FEV1 of ≥ 12% and ≥ 200 mL for participants ≥ 18 years of age OR a post-albuterol increase in FEV1 of ≥ 12% for participants 12 to < 18 years of age either in the 12 months prior to Visit 1 or at Visit 2 or Visit 3, if repeat testing is necessary.
7. A pre-bronchodilator/pre-dose FEV1 at Visits 2, 3, and 4 that has not changed 20% or more (increase or decrease) from the pre-bronchodilator/pre-dose FEV1 recorded at the previous visit.
8. Asthma stability during run-in based on Investigator discretion using the symptom worsening assessment defined in Section 8.1.2.8 as a guideline.
9. Willing and, in the opinion of the Investigator, able to adjust current asthma therapy, as required by the protocol.
10. Demonstrate acceptable MDI administration technique.
11. eDiary compliance ≥ 70% during screening, defined as completing the daily eDiary and answering "Yes" to taking 2 puffs of run-in BD MDI for any 10 mornings and 10 evenings in the last 14 days prior to randomization.

Exclusion criteria

1. Life-threatening asthma as defined as a history of significant asthma episode(s) requiring intubation associated with hypercapnia, respiratory arrest, hypoxic seizures, or asthma related syncopal episode(s).
2. Any respiratory infection or asthma exacerbation treated with systemic corticosteroids and/or additional ICS treatment in the 8 weeks prior to Visit 1 and throughout the Screening Period.
3. Hospitalization for asthma within 8 weeks of Visit 1.
4. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (eg, active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, and COPD). Significant is defined as any disease that, in the opinion of the Investigator, would put the safety of the participant at risk through participation, or that could affect the efficacy or safety analysis.
5. Known history of drug or alcohol abuse within 12 months of Visit 1.
6. Unresectable cancer that has not been in complete remission for at least 5 years prior to Visit 1. Note: Squamous cell and basal cell carcinomas of the skin are not exclusionary.
7. Participation in another clinical study with a study intervention administered in the last 30 days or 5 half-lives, whichever is longer. Any other study intervention that is not identified in this protocol is prohibited for use during study duration.
8. Previous or current randomization into studies within the AEROSPHERE program including KALOS, LOGOS, VATHOS, LITHOS, or any glycopyrronium studies (PT001).
9. Use of a nebulizer or a home nebulizer for receiving asthma medications. Note: Acute use of a nebulizer for an asthma exacerbation during hospitalization is allowed as long as there is no occurrence within 8 weeks of Visit 1.
10. Do not meet the stable dosing period prior to Visit 1 or unable to abstain from protocol-defined prohibited medications during Screening and Treatment Periods.
11. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, eg, vector, lipid nanoparticle) ≤7 days prior to Visit 1 (from last vaccination or booster dose).
12. Participants with known hypersensitivity to beta2-agonists, corticosteroids, or any component of the MDI.
13. Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or ECG, which in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study.
14. Current smokers, former smokers with > 10 pack-years history, or former smokers who stopped smoking < 6 months prior to Visit 1 (including all forms of tobacco, e-cigarettes or other vaping devices, and marijuana).
15. Planned hospitalization during the study.
16. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
17. Study Investigators, sub-Investigators, coordinators, and their employees or immediate family members.
18. Judgment by the Investigator that the participant is unlikely to comply with study procedures, restrictions and requirements.
19. For women only - currently pregnant (confirmed with positive highly sensitive urine pregnancy test), breast-feeding, or planned pregnancy during the study or not using acceptable contraception measures, as judged by the Investigator.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BFF MDI 160/9.6 μg BID (320/19.2μg/day); Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), BDI (320/19.2μg/day)	Drug: BFF MDI 160/9.6 μg BID (320/19.2μg/day); Budesonide/ Formoterol Fumarate (BFF) metered-dose inhaler (MDI), 160/9.6 μg BID (320/19.2μg/day); Other Names: BFF
Active Comparator: BD MDI 160 μg BID (320 μg/day); Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day)	Drug: BD MDI 160 μg BID (320 μg/day); Budesonide (BD) metered-dose inhaler (MDI), 160 μg BID (320 μg/day); Other Names: BD

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) Area Under the Curve 0 to 3 Hours (AUC0-3) at Week 12	Change from baseline in forced expiratory volume in 1 second (FEV1) area under the curve 0 to 3 hours (AUC0-3) at Week 12. FEV1 AUC0-3 is calculated from 0-3 hours post-dose using the trapezoidal rule, divided by the observation time to report the result in liters. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	At Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Morning Pre-dose Trough FEV1 at Week 12	Change from baseline in morning pre-dose trough FEV1 at Week 12. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	At Week 12
Onset of Action on Day 1: Absolute Change in FEV1 at 5 Minutes on Day 1	Onset of action on Day 1: Absolute change in FEV1 at 5 minutes on Day 1. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	On Day 1
Change From Baseline in the Mean Number of Puffs of Rescue Medication Use (Puffs/Day) Over 12 Weeks	Change from baseline in the mean number of puffs of rescue medication use (puffs/day) over 12 Weeks. Baseline is the average during the last 7 days before randomization. Over 12 weeks is the average from randomization up to week 12. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	Over 12 Weeks
Percentage of Responders in ACQ-7 (≥ 0.5 Decrease Equals Response) at Week 12	Percentage of responders in ACQ-7 at Week 12, where responders are defined as participants with a ≥0.5 decrease in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	At Week 12
Percentage of Responders in ACQ-5 (≥ 0.5 Decrease Equals Response) at Week 12	Percentage of responders in ACQ-5 at Week 12, where responders are defined as participants with a ≥0.5 decrease in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	At Week 12
Percentage of Responders in the Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(s) +12) (≥ 0.5 Increase Equals Response) at Week 12	Percentage of responders in the Asthma Quality of Life Questionnaire for 12 years and older (AQLQ(s)+12) at Week 12, where responders are defined as participants with a ≥0.5 increase in total score from baseline. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	At Week 12
Rate of Severe Asthma Exacerbation (Pooled LITHOS and VATHOS Data) During the Treatment Period (up to 24 Weeks)	As requested by a Health Authority, data from LITHOS and VATHOS (NCT05202262), two studies originally designed to assess lung function, were pooled to analyze the annualized rate of severe asthma exacerbations. This analysis was prespecified, uses data up to 12 weeks for LITHOS and 24 weeks for VATHOS, and was incorporated into the multiple testing procedure. An exacerbation is considered severe if it results in at least one of the following: a course of systemic corticosteroids (SCS) for ≥3 consecutive days to treat symptoms of asthma worsening, an ER or urgent care visit due to asthma requiring treatment with SCS, an in-patient hospitalization due to asthma, or death related to asthma. Treatment policy is implemented to handle all intercurrent events except for initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is used.	24 Weeks
Rate of Severe Asthma Exacerbation During the Treatment Period (up to 12 Weeks)	Annualized rate of severe asthma exacerbation during the treatment period (up to 12 Weeks). An asthma exacerbation will be considered severe if it results in at least one of the following: a course of systemic corticosteroids for at least 3 consecutive days to treat symptoms of asthma worsening, an ER or urgent care visit due to asthma that required treatment with systemic corticosteroids, an in-patient hospitalization due to asthma, or death related to asthma. Treatment policy is implemented to handle all intercurrent events with the exception of initiation of new asthma therapy or administration of prohibited medications thought to impact efficacy in conjunction with premature discontinuation of randomised study intervention, for which the composite strategy is implemented.	12 Weeks

Collaborators and Investigators

• Sponsor: AstraZeneca

Publications and helpful links

Helpful Links

• CSR Synopsis

Study record dates

Study Major Dates

• Study Start (Actual): February 27, 2023
• Primary Completion (Actual): November 19, 2024
• Study Completion (Actual): November 19, 2024

Study Registration Dates

• First Submitted: February 23, 2023
• First Submitted That Met QC Criteria: February 23, 2023
• First Posted (Actual): March 6, 2023

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 12, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Asthma; BID protein, human
• Other Study ID Numbers: D5982C00005; 2021-003334-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please rerefer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No