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)
Overview
- Phase
- Phase 1
- Intervention
- AZD8630
- Conditions
- Asthma
- Sponsor
- AstraZeneca
- Enrollment
- 170
- Locations
- 1
- Primary Endpoint
- Part A (IV cohort): Maximum observed serum (peak) drug concentration (Cmax) of AZD8630
- Status
- Completed
- Last Updated
- 2 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Part A (Healthy participants):
- •Healthy participants aged 18 to 55 years, inclusive:
- •Japanese participants must be aged 20 to 55 years, inclusive
- •Chinese participants must be aged 18 to 45 years, inclusive
- •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
- •Have a body mass index (BMI) between 18 and 30 kg/m\^2 inclusive and weigh at least 45 kg.
- •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.
- •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.
- •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.
- •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.
Exclusion Criteria
- •Part A (Healthy participants)
- •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.
- •Active or previous hepatitis B, hepatitis C, or Human immunodeficiency virus at the Screening Visit, and other latent or chronic infections.
- •History of severe COVID-19 (Coronavirus disease 2019) infection requiring hospitalization
- •SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) first vaccination within 30 days prior to screening.
- •SARS-CoV-2 second or booster vaccination within 10 days of screening.
- •Unwilling to defer SARS-CoV-2 vaccination during the study period.
- •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.
- •Have received live or live attenuated vaccine in 4 weeks prior to randomisation.
- •History of acquired or inherited immunodeficiency disorders including but not limited to HIV, COVID-19, or taking immune replacement therapy.
Arms & Interventions
Part A1: SAD (AZD8630)
Healthy participants will receive single inhaled doses 1 to 5 of AZD8630.
Intervention: AZD8630
Part A1: IV (AZD8630)
Healthy participants will receive a single IV dose of AZD8630.
Intervention: AZD8630
Part A1: IV (Placebo)
Healthy participants will receive single IV dose of Placebo.
Intervention: Placebo
Part A2: SAD (AZD8630)
Healthy participants of Chinese and Japanese ethnicity will receive single inhaled dose 5 of AZD8630.
Intervention: AZD8630
Part A3: MAD (AZD8630)
Healthy participants will receive once daily inhaled doses 3, 4, and 5 of AZD8630.
Intervention: AZD8630
Part A4: MAD (AZD8630)
Healthy participants of Chinese and Japanese ethnicity will receive once daily inhaled dose 5 of AZD8630.
Intervention: AZD8630
Part A: SAD (Placebo)
Healthy participants and healthy participants of Chinese and Japanese ethnicity will receive single inhaled doses of placebo.
Intervention: Placebo
Part A: MAD (Placebo)
Healthy participants and healthy participants of Chinese and Japanese ethnicity will receive once daily inhaled dose of placebo.
Intervention: Placebo
Part B (AZD8630)
Participants with asthma will be randomized to one of 3 inhaled dose levels 3, 6, and 7 of AZD8630 once daily.
Intervention: AZD8630
Part B (Placebo)
Participants with asthma will receive once daily inhaled dose of placebo.
Intervention: Placebo
Outcomes
Primary Outcomes
Part A (IV cohort): Maximum observed serum (peak) drug concentration (Cmax) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
Cmax of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV cohort): Time of last observed quantifiable concentration (tlast) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
tlast of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed
Part A (IV cohort): Terminal rate constant (λz) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
λz of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A and Part B: Number of participants with adverse events
Time Frame: 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)
Safety and tolerability of inhaled AZD8630 in healthy participants and participants with asthma will be assessed.
Part A (IV cohort): Time to reach maximum observed concentration (tmax) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
tmax of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed
Part A (IV cohort): Area under serum concentration-time curve from zero to infinity (AUCinf) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
AUCinf of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
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
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
AUC(0-24) of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV cohort): Area under the serum concentration curve from zero to the last quantifiable concentration (AUClast) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
AUClast of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV cohort): Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
t1/2λz) of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV Cohort): Number of participants with adverse events
Time Frame: Until Follow-up (FU) Visit/Early Termination (ET) Visit (7-day post-dose)
Safety and tolerability of IV AZD8630 in healthy participants will be assessed.
Part A (IV cohort): Total body clearance of drug from serum after IV administration (CL) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
CL of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV cohort): Volume of distribution at steady state (Vss) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
Vss of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV cohort): Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
MRTinf of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Part A (IV Cohort): Volume of distribution of drug from serum after IV administration (Vz) of AZD8630
Time Frame: Pre-dose and Post-dose on Days 1 to 4 and Follow-up Visit/ET Visit (7-day post-dose)
Vz of AZD8630 following IV administration of single dose of AZ8630 in healthy participants will be assessed.
Secondary Outcomes
- Part A and Part B: Time to reach maximum observed concentration (tmax) of AZD8630(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))
- Part A (A1 and A2 only): Time of last observed quantifiable concentration (tlast) of AZD8630(Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose))
- Part A and Part B: Apparent total body clearance of drug from serum after extravascular administration (inhalation administration only) [CL/F] of AZD8630(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))
- Part A and Part B: Concentration at the end of the dosing interval (Ctrough) [repeat dose only] of AZD8630(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))
- Part A and Part B: Maximum observed serum (peak) drug concentration (Cmax) of AZD8630(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))
- Part A and Part B: Maximum observed serum (peak) drug concentration divided by the lung-delivered dose (LDD) [Cmax/D] of AZD8630(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))
- 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(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)
- 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(Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose))
- Part A and Part B: Area under serum concentration-time curve from zero to infinity (AUCinf) of AZD8630(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)
- Part B: Change from baseline in fractional exhaled nitric oxide (FeNO) levels(From Screening (Up to days 28 before Day 1) until Day 29 (end of the treatment visit))
- Part A: Area under the serum concentration curve from zero to the last quantifiable concentration (AUClast) of AZD8630(Pre-dose and Post-dose: Part A- (SAD) Days 1 to 4 and FU Visit/ET Visit (7-day post-dose))
- 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(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)
- Part A and Part B: Half-life associated with terminal slope (λz) of a semi-logarithmic concentration-time curve (t1/2λz) of AZD8630(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))
- Part A and Part B: Apparent volume of distribution following extravascular administration based on terminal phase (inhalation administration only) [Vz/F] of AZD8630(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))
- Part A and Part B: Accumulation ratio based upon AUCt [Rac(AUC)] of AZD8630(Pre-dose and Post-dose: Part A- (MAD) Day 14; Part B- Day 28)
- Part A and Part B: Number of participants with presence of anti-drug antibodies (ADAs)(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))
- 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(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)
- Part A and Part B: Area under serum concentration-time curve in the dosing interval t (AUCt) of AZD8630(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))
- Part A and Part B: Area under serum concentration-time curve in the dosing interval t divided by the LDD (AUCt/D) of AZD8630(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))
- Part A and Part B: Terminal rate constant (λz) of AZD8630(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))
- Part A and Part B: Mean residence time of the unchanged drug in the systemic circulation (MRTinf) of AZD8630(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))
- Part A and Part B: Accumulation ratio based upon Cmax [Rac(Cmax)] of AZD8630(Pre-dose and Post-dose: Part A- (MAD) Day 14; Part B- Day 28)