Clinical trial NCT05850494: Study to Assess Bronchospasm Potentially Induced by HFO vs HFA MDI in Participants With Well/Partially Controlled Asthma
Official title: Randomized, DB, Crossover Study to Assess Bronchospasm Potentially Induced by HFO MDI vs. HFA MDI Propellant in Participants With Asthma Well/Partially Controlled on SABA With or Without Low-Dose ICS
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Asthma, Bronchospasm
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2023-05-09
Enrollment: 52
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: The purpose of this study is to assess bronchospasm potentially induced by hydrofluoroolefin (HFO) metered dose inhaler (MDI) as compared with hydrofluoroalkane (HFA) MDI in participants with asthma, well controlled or partially controlled on treatment for asthma, including, low-dose inhaled corticosteroid (ICS) daily or low-dose ICS/formoterol as needed (not approved in the US), or short-acting beta2-agonists (SABA) as needed, or low-dose ICS whenever SABA as needed is used.

Study details include:

* The study duration will be up to 37 days.
* The treatment duration will be 1 day for each treatment period.
* The visit frequency will be approximately every 1 week.
Primary purpose: TREATMENT

Brief summary: A study to assess bronchospasm potentially induced by HFO MDI as compared with HFA MDI in participants with well controlled or partially controlled asthma

Detailed description: This is a phase 3b, multicentre, randomized, double-blind, single-dose crossover study comparing the safety and tolerability of HFO MDI with HFA MDI delivered in participants with well controlled or partially controlled asthma defined as an ACQ-5 score \< 1.5.Eligible participants are at least 18 years of age and no older than 45 years of age and are required to have asthma as defined by GINA guidelines (GINA 2022). Participants are required to be well controlled or partially controlled on their current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used. The primary objective is to assess the potential change in FEV1 induced by HFO MDI as compared with HFA MDI in participants with asthma.

This study will be conducted at approximately 5 sites in the US and will randomize approximately 52 adult participants to achieve 46 completers.

The study will be conducted for a maximal 37 days and will comprise:

* A screening period approximately 14 (±2) days prior to first dosing
* Two treatment periods of 1 day each, with a 3 to 12-day washout period between the 2 treatment periods
* A final safety follow-up visit via telephone contact 3 to 7 days after the final dose administration in Treatment Period 2

Single dose study treatment will be administered via MDI device as 4 inhalations:

* Treatment A: HFO propellant only MDI; 4 inhalations per dose - test formulation
* Treatment B: HFA propellant only MDI; 4 inhalations per dose - reference formulation

Eligibility criteria: Inclusion Criteria:

* Age

  1. Male and female participant must be 18 to 45 years of age inclusive, at the time of signing the informed consent form (ICF).

     Type of Participant and Disease Characteristics
  2. Participants who have a documented history of physician-diagnosed asthma

     ≥ 12 months prior to Visit 1, according to GINA guidelines (GINA 2022).
  3. Participants who are well controlled or partially controlled on their current treatment for asthma, including, low-dose ICS daily or low-dose ICS/formoterol as needed (not approved in the US), or SABA as needed, or low-dose ICS whenever SABA as needed is used (low-dose ICS as defined by GINA 2022 in Table 4), for 4 weeks prior to screening.
  4. ACQ-5 total score \< 1.5 at Visit 1.
  5. A pre-bronchodilator FEV1 \> 60% predicted normal value at Visit 1.
  6. Demonstrate acceptable MDI administration technique.

     Sex and Contraceptive/Barrier Requirements
  7. Females must be not of childbearing potential, or should be 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 included in this study will 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.
* Female participants of childbearing potential must use one 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. At enrolment, women of childbearing potential who are sexually active with a non-sterilized male partner should be stable on their chosen method of highly effective birth control, as defined below, and willing to remain on the birth control until at least 14 days after last dose of study intervention. Cessation of contraception after this point should be discussed with a responsible physician.

Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception. Female condom and male condom should not be used together. All women of childbearing potential must have a negative serum pregnancy test result at Visit 1.

* Highly effective birth control methods are listed below:
* Total sexual abstinence is an acceptable method provided it is the usual lifestyle of the participant (defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments). Periodic abstinence (e.g., 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 or progesterone only)
* Injectable progestogen
* Contraceptive vaginal ring
* Percutaneous contraceptive patches
* 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. 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 8 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.

Exclusion Criteria:

* Medical Conditions

  1. Life-threatening asthma 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. 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).
  3. Historical or current evidence of a clinically significant disease including, but not limited to: cardiovascular, hepatic, renal, hematological, neurological, endocrine, gastrointestinal, or pulmonary (e.g., active tuberculosis, bronchiectasis, pulmonary eosinophilic syndromes, COPD, and uncontrolled severe asthma). 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 safety/tolerability analysis.
  4. 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.
  5. Hospitalization for asthma within 1 year prior to Visit 1.
  6. Admission to intensive care unit or mechanical ventilation due to asthma exacerbation.
  7. Known history of drug or alcohol abuse within 12 months of Visit 1.

     Prior/Concomitant Therapy
  8. Do not meet the stable dosing period prior to Visit 1 (see Table 5) or unable to abstain from protocol-defined prohibited medications during screening and treatment periods (see Table 6 and Table 7).
  9. Receipt of COVID-19 vaccine (regardless of vaccine delivery platform, e.g., vector, lipid nanoparticle) ≤ 7 days prior to Visit 1 (from last vaccination or booster dose).

Prior/Concurrent Clinical Study Experience 10 Participation in another clinical study with an investigational product administered within 30 days or 5 half-lives (whichever is longer). 11 Participants with a known hypersensitivity to HFO or HFA or any of the excipients of the product. 12 Previously randomized into a study with an HFO-containing MDI.

Diagnostic Assessments 13 Any clinically relevant abnormal findings in physical examination, clinical chemistry, hematology, urinalysis, 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 QT 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 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 15 Judgment by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements.

16 Previous enrolment or randomisation in the present study. 17 For women only - currently pregnant (confirmed with positive pregnancy test), breast feeding, or planned pregnancy during the study or women of childbearing potential not using acceptable contraception measures. 18 Study investigators, sub-investigators, coordinators, and their employees or immediate family members.

Primary outcomes:
measure: Change from baseline FEV1 to 15-min post-dose
timeFrame: up to 36 days
Secondary outcomes:
measure: Cumulative incidence of bronchospasm events
timeFrame: up to 36 days
measure: Safety and tolerability will be evaluated in terms of AEs
timeFrame: up to 36 days
Other outcomes:
measure: Repeated measurements of change from baseline in FEV1 at 5, 15, and 30 minutes post-dose during each treatment period
timeFrame: up to 36 days
Locations:
city: North Dartmouth
country: United States
facility: Research Site
state: Massachusetts
city: Saint Louis
country: United States
facility: Research Site
state: Missouri
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: El Paso
country: United States
facility: Research Site
state: Texas
Study officials:
affiliation: Northeast Medical Research Associates, Inc.
name: David Miller, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: North Carolina Clinical Research
name: Craig LaForce, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: EPIMRD Inc.
name: Allen T Funkhouser, MC
role: PRINCIPAL_INVESTIGATOR
affiliation: The Clinical Research Center, LLC.
name: Jeffrey Tillinghast, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buhl R, Tanase AM, Hosoe M, Cao W, Demin I, Bartels C, Jauernig J, Ziegler D, Patalano F, Hederer B, Kanniess F, Tillmann HC. A randomized, double-blind study to compare the efficacy and safety of two doses of mometasone furoate delivered via Breezhaler(R) or Twisthaler(R) in patients with asthma. Pulm Pharmacol Ther. 2020 Jun;62:101919. doi: 10.1016/j.pupt.2020.101919. Epub 2020 May 7.
citation: Global Initiative for Asthma (GINA). Global Strategy for Asthma Management and Prevention, 2022. http://ginasthma.org.
citation: 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.
citation: Investigator's Brochure - Budesonide, Glycopyrronium and Formoterol Fumarate Inhalation Aerosol (BGF MDI); Budesonide and Formoterol Fumarate Inhalation Aerosol (BFF MDI); Budesonide Inhalation Aerosol (BD MDI); Glycopyrronium Inhalation Aerosol (GP MDI) (Also known as PT010 [BGF MDI], PT009 [BFF MDI], PT008 (BD MDI); PT001 (GP MDI); Edition Number 9.0, 16 September 2022.
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.
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.
citation: Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J; ATS/ERS Task Force. Standardisation of spirometry. Eur Respir J. 2005 Aug;26(2):319-38. doi: 10.1183/09031936.05.00034805. No abstract available.
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.
citation: Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5-40. No abstract available.