Clinical trial NCT05110976: A Study to Investigate the Safety, Tolerability and Effects of AZD8630 in Healthy Subjects and Subjects With Asthma on Inhaled Corticosteroids and Long-acting Beta-agonists
Official title: Phase I, Randomised, Blinded, Placebo-controlled Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of AZD8630 in Healthy Adult Subjects (Part A) and Adults With Asthma on Medium to High Dose Inhaled Corticosteroids and Long-acting Beta-agonists (Part B)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Asthma
Keywords: Healthy adult participants
Healthy participants of Chinese and Japanese ethnicity
Corticosteroids Beta-agonists
Multiple ascending dose
Single ascending dose
Lead sponsor: AstraZeneca
Sponsor class: INDUSTRY
First posted: 2021-11-08
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: OTHER

Brief summary: This is a first in human (FIH) clinical study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of AZD8630 in healthy adults (Part A) and adult asthma patients on medium to high dose inhaled corticosteroids / Long-acting beta-agonists (Part B)

Detailed description: The study is divided in 2 parts, A and B.

Part A will be conducted in healthy adults, whereas Part B will be conducted in adult asthma patients on medium/high dose inhaled corticosteroids (ICS)/long-acting beta-agonists (LABA) to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of AZD8630 by dry powder inhaler (DPI) administration. Part A includes the assessment of the PK and safety of intravenous (IV) AZD8630. Part A consists of single ascending dose (SAD) and multiple ascending dose (MAD) cohorts in sequential order and Part B will be evaluating multiple dose levels.

Part A: This part will consist 4 sub-parts and will include healthy participants and healthy participants of Chinese and Japanese ethnicity. These participants will randomized to receive AZD8630 and to receive placebo.

* Sub-Part A1, SAD in healthy participants (one cohort in Sub-Part A1 will receive IV AZD8630 \[IV formulation\])
* Sub-Part A2, SAD in healthy participants of Chinese and Japanese ethnicity
* Sub-Part A3, MAD in healthy participants
* Sub-Part A4, MAD in healthy participants of Chinese and Japanese ethnicity

Part B: Adult asthma patients will be randomized to one of 3 inhaled dose levels of AZD8630 or placebo.

The expected duration of study participation for each participants in the part A is up to 87 days, and each patients in the Part B is up to 70 days.

Eligibility criteria: Inclusion Criteria:

Part A (Healthy participants):

1. Healthy participants aged 18 to 55 years, inclusive:

   1. Japanese participants must be aged 20 to 55 years, inclusive
   2. Chinese participants must be aged 18 to 45 years, inclusive
2. Females must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test on admission to the Clinical Unit, must not be lactating, and must be of non childbearing potential, confirmed at the Screening Visit
3. Have a body mass index (BMI) between 18 and 30 kg/m\^2 inclusive and weigh at least 45 kg.
4. Healthy participant must have a forced expiratory volume in 1 second (FEV1) ≥ 80% of the predicted value regarding age, height, gender, and ethnicity at the Screening Visit.
5. Male participants and their women of childbearing potential partners (WOCPB) should be willing to use highly effective contraception measures and male participants should refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the study Follow up Visit.
6. Part A2 and Part A4 (Chinese population only): Chinese participants must have been born in China, have all parents and grandparents of Chinese origin, and not have lived outside of China for more than 10 years.
7. Part A2 and Part A4 (Japanese population only): Japanese participants must have been born in Japan, have all parents and grandparents of Japanese origin, and not have lived outside of Japan for more than 10 years.

Part B (Participants with Asthma):

1. Male and female including WOCBP participants with asthma aged 18 to 75 years inclusive, with suitable veins for cannulation or repeated venipuncture.
2. Have a BMI between 18 and 35 kg/m\^2 inclusive and weigh at least 45 kg.
3. Confirmed physician-led diagnosis of asthma for \> 6 months before the Screening Visit.
4. Any of the following assessments within the last 10 years to confirm variable airflow obstruction: Variability between clinic visits: FEV1 \> 12% and 200 mL; Response to 4 weeks' anti-inflammatory therapy: FEV1 \> 12% and 200 mL; Exercise challenge test: FEV1 fall \> 10% and 200mL; Methacholine challenge test: FEV1 ≥ 20% fall at \< 8 mg/mL; Indirect challenge test: FEV1 ≥ 15% fall; Or in the screening period: Variability between clinic visits: FEV1 \> 12% and 200 mL; Peak expiratory flow rate (PEFR) for 2 weeks during run-in: PEFR average daily variability \> 10%.
5. Pre-bronchodilator FEV1 ≥ 40% and \< 85% predicted at the Screening Visit.
6. Have a fractional exhaled nitric oxide (FeNO) of ≥ 35 ppb at the Screening Visit and ≥ 30 ppb at randomisation.
7. Asthma Control Questionnaire -5 score of ≥ 0.75 and ≤ 3.0 at screening.
8. During 7 consecutive days within screening, immediately prior to randomisation demonstrates ≥ 65% adherence to each of the following:

   1. Once daily home FeNO
   2. Twice daily home spirometry measurements
   3. Twice daily entries in the eDiary
9. Females must have a negative serum pregnancy test at the Screening Visit. Additionally, WOCBP must have a negative urine pregnancy test at Visit 2 (prior to randomisation) and must not be lactating.
10. Male participants and their WOCBP partners should be willing to use highly effective contraception measures and male participants should refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the study Follow-up Visit.
11. WOCBP must be willing to use highly effective contraception measures from the first day of dosing until 3 months after the study Follow up Visit.

Exclusion Criteria:

Part A (Healthy participants)

1. History of following: any clinically important disease or disorder; any upper or lower respiratory tract infection during screening period; active tuberculosis or current positive result for Interferon gamma release assay at screening; clinically significant history of atopy or allergy to common allergens including house dust mite and pollens, or a history of childhood asthma.
2. Active or previous hepatitis B, hepatitis C, or Human immunodeficiency virus at the Screening Visit, and other latent or chronic infections.
3. History of severe COVID-19 (Coronavirus disease 2019) infection requiring hospitalization
4. SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) first vaccination within 30 days prior to screening.
5. SARS-CoV-2 second or booster vaccination within 10 days of screening.
6. Unwilling to defer SARS-CoV-2 vaccination during the study period.
7. History of cancer within last 10 years (20 years for breast cancer) except for basal and squamous cell carcinoma of skin or in situ carcinoma of cervix treated and considered cured. Any history of lymphoma is not allowed.
8. Have received live or live attenuated vaccine in 4 weeks prior to randomisation.
9. History of acquired or inherited immunodeficiency disorders including but not limited to HIV, COVID-19, or taking immune replacement therapy.
10. C-reactive protein above upper limit of laboratory reference range
11. Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results and abnormal vital signs at the Screening Visit.
12. Current smokers or those who have smoked or used nicotine or inhalational cannabis/marijuana products. History of alcohol abuse or drug abuse.
13. Use of any prescribed or nonprescribed medication during the 2 weeks prior to the first administration of investigational medicinal product.
14. Has received another new chemical entity.
15. History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity, as judged by the investigator, or history of hypersensitivity to drugs with a similar chemical structure or class to AZD8630.
16. History of anaphylaxis to any previous biological therapy.
17. Participants who have previously received AZD8630.

Part B (Participants with Asthma):

1. History of following: any clinically important disease or disorder; any chronic respiratory disorders (except asthma) such as Chronic obstructive pulmonary disease, bronchiectasis, or IPF; clinically significant lower respiratory tract infection not resolved within 4 weeks prior to screening.
2. Acute exacerbation of asthma requiring hospitalisation and/or attendance at an emergency department and/or systemic corticosteroids within 6 weeks of randomisation.
3. History of active TB or a current positive result for IGRA at screening.
4. History of severe COVID-19 infection requiring hospitalisation.
5. SARS-CoV-2 first vaccination within 30 days prior to screening.
6. SARS-CoV-2 second or booster vaccination within 10 days of screening.
7. Confirmed COVID-19 infection during screening, prior to randomisation.
8. History of cancer within the last 10 years (20 years for breast cancer) except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured. Any history of lymphoma is not allowed.
9. Have received live or live attenuated vaccine in the 4 weeks prior to randomisation.
10. C-reactive protein above the upper limit of laboratory reference range at screening.
11. Any clinically important abnormalities in clinical chemistry, haematology or urinalysis results, and abnormal vital signs at the Screening Visit.
12. Current smokers or those who have smoked or used nicotine or inhalational cannabis/marijuana products. History of alcohol or drug abuse.
13. Positive screen for drugs of abuse or cotinine (nicotine) prior to randomisation.
14. Use of drugs with enzyme inducing properties such as St John's Wort within 3 weeks before first administration of study drug.
15. Use of any prescribed or nonprescribed medication during the 2 weeks prior to the first administration of study drug.
16. Use of following medicines within specified time before Screening: (a) Any biologics for asthma within 6 months prior to Screening; (b) Systemic or intranasal steroids within 4 weeks prior to Screening; (c) Xanthines, anticholinergics, or cromoglycate within 1 week prior to Screening; (d) Short acting bronchodilator other than for rescue and within 12 hours prior to Screening and Day -1 assessments.
17. History of anaphylaxis or ongoing clinically important serious allergy, or history of hypersensitivity or anaphylaxis to drugs with a similar chemical structure or class to AZD8630.
18. History of anaphylaxis to any previous biological therapy.
19. Pregnancy or intention to become pregnant during course of study, breastfeeding, or unwillingness to use a highly effective method of contraception throughout study in female participants of childbearing potential or lactating woman.

Primary outcomes:
measure: Part A and Part B: Number of participants with adverse events
timeFrame: Until Follow-up (FU) Visit/Early Termination (ET) Visit (Part A: 7-day post-dose for SAD; 10-day post-last dose for MAD) and Part B: Until FU Visit/ET Visit (10-day post-last dose)
measure: Part A (IV cohort): Time to reach maximum observed concentration (tmax) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Time of last observed quantifiable concentration (tlast) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Maximum observed serum (peak) drug concentration (Cmax) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Partial area under the serum concentration-time curve from 0 to time 24 hours post-dose [AUC(0-24)] of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Area under the serum concentration curve from zero to the last quantifiable concentration (AUClast) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Area under serum concentration-time curve from zero to infinity (AUCinf) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Terminal rate constant (λz) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Total body clearance of drug from serum after IV administration (CL) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV cohort): Volume of distribution at steady state (Vss) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV Cohort): Volume of distribution of drug from serum after IV administration (Vz) of AZD8630
timeFrame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
measure: Part A (IV Cohort): Number of participants with adverse events
timeFrame: Until Follow-up (FU) Visit/Early Termination (ET) Visit (7-day post-dose)
Secondary outcomes:
measure: Part A and Part B: Time to reach maximum observed concentration (tmax) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A (A1 and A2 only): Time of last observed quantifiable concentration (tlast) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose)
measure: Part A and Part B: Maximum observed serum (peak) drug concentration (Cmax) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Maximum observed serum (peak) drug concentration divided by the lung-delivered dose (LDD) [Cmax/D] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Concentration at the end of the dosing interval (Ctrough) [repeat dose only] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Partial area under the serum concentration-time curve from 0 to time 24 hours post-dose [AUC(0-24)] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), and Day 1 for MAD and Part B
measure: Part A and Part B: Partial area under the serum concentration-time curve from 0 to time 24 hours post-dose divided by the LDD [AUC(0-24)/D] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), and Day 1 for MAD and Part B
measure: Part A: Area under the serum concentration curve from zero to the last quantifiable concentration (AUClast) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose)
measure: Part A: Area under the serum concentration-time curve from time zero to time of last quantifiable drug concentration divided by the LDD (AUClast/D) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose)
measure: Part A and Part B: Area under serum concentration-time curve from zero to infinity (AUCinf) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), and Day 1 for MAD and Part B
measure: Part A and Part B: Area under the serum concentration-time curve from time zero extrapolated to infinity divided by the LDD (AUCinf /D) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), and Day 1 for MAD and Part B
measure: Part A and Part B: Area under serum concentration-time curve in the dosing interval t (AUCt) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Area under serum concentration-time curve in the dosing interval t divided by the LDD (AUCt/D) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Terminal rate constant (λz) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Apparent total body clearance of drug from serum after extravascular administration (inhalation administration only) [CL/F] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Apparent volume of distribution following extravascular administration based on terminal phase (inhalation administration only) [Vz/F] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1 to 14, Day 28, Day 29, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part A and Part B: Accumulation ratio based upon AUCt [Rac(AUC)] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (MAD) Day 14; Part B- Day 28
measure: Part A and Part B: Accumulation ratio based upon Cmax [Rac(Cmax)] of AZD8630
timeFrame: Pre-dose and Post-dose: Part A- (MAD) Day 14; Part B- Day 28
measure: Part A and Part B: Number of participants with presence of anti-drug antibodies (ADAs)
timeFrame: Pre-dose: Part A- (SAD) Days 1 to 3 and FU Visit/ET Visit (7-day post-dose), (MAD) Days 1 to 17 and FU Visit/ET Visit (10-day post-last dose); Part B- Days 1, 7, 14, and 28, and FU Visit/ ET Visit (10-day post-last dose)
measure: Part B: Change from baseline in fractional exhaled nitric oxide (FeNO) levels
timeFrame: From Screening (Up to days 28 before Day 1) until Day 29 (end of the treatment visit)
Other outcomes:
Locations:
city: Tempe
country: United States
facility: Research Site
state: Arizona
city: Bakersfield
country: United States
facility: Research Site
state: California
city: Glendale
country: United States
facility: Research Site
state: California
city: San Jose
country: United States
facility: Research Site
state: California
city: Homestead
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Miami
country: United States
facility: Research Site
state: Florida
city: Boise
country: United States
facility: Research Site
state: Idaho
city: White Marsh
country: United States
facility: Research Site
state: Maryland
city: North Dartmouth
country: United States
facility: Research Site
state: Massachusetts
city: Ann Arbor
country: United States
facility: Research Site
state: Michigan
city: Raleigh
country: United States
facility: Research Site
state: North Carolina
city: Toledo
country: United States
facility: Research Site
state: Ohio
city: Portland
country: United States
facility: Research Site
state: Oregon
city: El Paso
country: United States
facility: Research Site
state: Texas
city: Berlin
country: Germany
facility: Research Site
city: Frankfurt
country: Germany
facility: Research Site
city: Großhansdorf
country: Germany
facility: Research Site
city: Lübeck
country: Germany
facility: Research Site
city: Magdeburg
country: Germany
facility: Research Site
city: Wiesbaden
country: Germany
facility: Research Site
city: Bradford
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: London
country: United Kingdom
facility: Research Site
city: Manchester
country: United Kingdom
facility: Research Site
city: Portsmouth
country: United Kingdom
facility: Research Site
Study officials:
References: