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Number
D5982C00005

Type
Asthma

Age Range
Adolescent / Adult 

Length of study
​Approx. 12 weeks

​Compensation
Time/Travel

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)   

​​Criteria
Inclusion Criteria:
Participants are eligible to be included in the study only if all of the following criteria apply:
Age
1 Participant must be 12 to 80 years of age inclusive, at the time of signing the ICF. Note: For participants 12 to < 18 years of age, their parents or legal guardians must give their signed written informed consent, as appropriate, and participants will sign an assent form.

Type of Participant and Disease Characteristics
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 1 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 the ICS doses allowed in Table 6, 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).
Note: Participants who have not withheld asthma medications prior to Visit 1 and failed spirometry testing at Visit 1 should return to the clinic to repeat spirometry testing within 2 business days. If repeat spirometry fails, then participants must be screen failed.
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 of 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.

Note: Regardless of availability of documented history of reversibility, all participants must be assessed for reversibility at Visit 2 (and Visit 3, if reversibility is not demonstrated at Visit 2) to provide reversibility baseline data for characterization.
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.
Note: Historical use of a spacer device within the 8 weeks prior to and/or during the Screening and Randomized Treatment Periods is not permitted.
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.

Weight
12 Body mass index < 40 kg/m2.

Sex
13 Male and/or female; females must be not of childbearing potential or using a form of highly effective birth control as defined below: Female participants: Women not of childbearing potential are defined as women who are either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral
salpingectomy), or who are postmenopausal. Women will be considered postmenopausal if they have been amenorrhoeic for 12 months prior to the planned
date of randomization without an alternative medical cause. The following age-specific requirements apply:
   -Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of
                exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range.
             -Women ≥ 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all 
               exogenous hormonal treatment.
            Female participants of childbearing potential must use a highly effective form of birth control. A highly effective method of contraception is defined as
            one that can achieve a failure rate of less than 1% per year when used consistently and correctly. Women of childbearing potential who are sexually active 
            with a non-sterilized male partner must agree to use a highly effective method of birth control, as defined below, from enrollment throughout the study
            and until at least 16 weeks after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible
            physician. All women of childbearing potential must have a negative highly sensitive urine (at all visits). Adolescent participants should be counselled
            appropriately by the Investigator.

 Highly effective birth control methods are listed below:
        - Sexual abstinence defined as complete abstinence from intercourse when it is the preferred and usual lifestyle of the participant (however, periodic
            abstinence eg, calendar, ovulation, symptothermal, post-ovulation methods, declaration of abstinence for the duration of exposure to study intervention,
            and withdrawal are not acceptable methods of contraception)
        - Contraceptive subdermal implant
        - Intrauterine device or intrauterine system
        - Oral contraceptive (combined and progesterone only)
        - Injectable progestogen [Hatcher 2011]
        - Contraceptive vaginal ring [Hatcher 2011]
        - Percutaneous contraceptive patches [Hatcher 2011]
        - Male partner sterilization with documentation of azoospermia prior to the female participant’s entry into the study, and this male is the sole partner for
            that participant [Hatcher 2011]. The documentation on male sterility can come from the site personnel’s review of participant’s medical records, medical
            examination and/or semen analysis or medical history interview provided by her or her partner.
        - Bilateral tubal ligation

Informed Consent
14 Capable of giving signed informed consent as described in Appendix A which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
15 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports Genomic Initiative.
​
Exclusion Criteria:
Participants are excluded from the study if any of the following criteria apply:

Medical Conditions
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.

Prior/Concomitant Therapy
7 Participation in another clinical study with an Investigational Product administered in the last 30 days or 5 half-lives, whichever is longer. Any other Investigational Product that is not identified in this protocol is prohibited for use during study duration.
8 Previous or current randomization in any budesonide and formoterol fumarate or budesonide, glycopyrronium, and formoterol fumarate studies (PT009 or PT010).
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 (see Table 7) or unable to abstain from protocol-defined prohibited medications during Screening and Treatment Periods (see Table 8 and Table 9).
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.

Diagnostic Assessments
13 Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, vital signs, or electrocardiogram (ECG), which in the opinion of the Investigator, may put the participant at risk because of his/her participation in the study.
Note: Participants with ECG QTcF interval (corrected for heart rate using Fridericia’s formula [QTcF]) > 480 msec will be excluded. Participants with high degree
atrioventricular block II or III, or with sinus node dysfunction with clinically significant pauses who are not treated with pacemaker will also be excluded.
​
Other Exclusions
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.