A Clinical Trial in Healthy Volunteers and Patients With Mild Asthma to Investigate a New Medicine (AZD4604) for the Treatment of Asthma
- Conditions
- Asthma
- Interventions
- Drug: AZD4604 for inhalation via DPIDrug: AZD4604 for oral administrationDrug: AZD4604 for IV administrationDrug: Placebo for AZD4604 for inhalation via DPI
- Registration Number
- NCT04769869
- Lead Sponsor
- AstraZeneca
- Brief Summary
This is a first in human clinical study. Part 1 of the clinical study will assess the safety and tolerability, as well as the single dose pharmacokinetics (PK), of inhaled AZD4604 in healthy volunteers (Part 1a, single ascending dose \[SAD\]). The single dose administration will be performed with dry powder inhaler (DPI) formulation of AZD4604. When at least 4 cohorts of the SAD part of the study have been completed, AZD4604 will be administered as a single intravenous (IV) or oral (PO) dose to 2 different cohorts of healthy volunteers (Part 1b). The main purpose is to compare the PK between IV, oral and inhaled administration to further characterize the PK properties of AZD4604 by the various administration routes. The results will be used to improve future study design and interpretation. In Part 2 (Multiple ascending dose \[MAD\]), AZD4604 will be administered at multiple doses (twice daily \[BID\], 7 days) to healthy volunteers. In Part 3, AZD4604 will be administered at multiple doses to patients with mild asthma at dose levels assessed in Part 2. The multiple-dose administration will be performed with DPI-formulated AZD4604.
- Detailed Description
Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study. Seven inhaled dose levels of AZD4604 are planned to be investigated in cohorts of 8 healthy volunteers, with 6 healthy volunteers randomly assigned to inhaled AZD4604 and 2 healthy volunteers randomly assigned to inhaled placebo in each cohort.
Part 1a will comprise of:
* A Screening Visit within 28 days before dosing.
* A Treatment Period (Day -1 to Day 7, in the Clinical Unit) with a single inhaled dose of AZD4604 or corresponding placebo on Day 1. Although the anticipated systemic exposure and risk for potential adverse systemic effects are considered to be low for AZD4604, healthy volunteers will remain resident at site for additional 6 days of monitoring.
* A Final Assessment on day of discharge.
In Part 1b, AZD4604 will be administered as a single IV or a PO dose to healthy volunteers in order to compare the PK between IV, PO and inhaled administration. Part 1b will be open-label and consist of 2 dose cohorts, IV and PO, with 6 healthy volunteers in each.
Part 1b will comprise of:
* A washout period of at least 2 weeks for the healthy volunteers who received inhaled dosing in Part 1a will occur before IV or PO dosing in Part 1b. All healthy volunteers will have a Screening Visit within 28 days of dosing.
* A Treatment Period (Day -1 to Day 3, in the Clinical Unit) with a single IV or PO dose of AZD4604 on Day 1.
* A Follow-up Visit within 6 ± 1 day after dosing.
Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design. This part of the study will be conducted in up to 32 healthy volunteers.
Part 2 will comprise of:
* A Screening Visit within 28 days before first dosing.
* A Treatment Period (Day -1 to Day 12 in the Clinical Unit) with twice daily (BID) inhaled doses of AZD4604 or placebo on Day 1 to Day 6 (12-hour \[+/- 30 minutes\] intervals between doses), and a single inhaled dose on Day 7. The healthy volunteers will remain resident at site for additional 6 days of monitoring, which is predicted to allow sufficient time for near complete washout (estimated time for \> 97% of the dose to have been eliminated) of any target engagement from the lungs. Healthy volunteers will remain in the Clinical Unit for the duration of the treatment period and will be discharged on Day 13, 6 days after administration of the last dose.
* A Final Assessment on day of discharge.
Part 3 of the study will be a randomized, single-blind, placebo-controlled, multiple-dose, PK and pharmacodynamic (PD) study part, with daily non-residential visits during the Treatment Period. This part of the study will be conducted in at least 45 patients with mild asthma (16 patients in Cohorts 1 and 2 and at least 29 patients in the Proof of Mechanism \[PoM\] Cohort).
Part 3 will comprise of:
* A Screening Visit within 42 days before first dosing.
* A Treatment Period (Day -3 to Day 15 as daily non-residential visits) with BID inhaled doses of AZD4604 or placebo on Day 1 to Day 9 (12-hour intervals between doses), and a single inhaled dose on Day 10. Dosing will take place at the clinical site and patients will need to visit the site twice daily on Day 1 to Day 9. The anticipated systemic exposure and risk for potential adverse systemic effects are considered to be low for AZD4604, therefore, patients will not be required to be resident at site during the Treatment Period.
* A Final Assessment (Day 16) on the last day of the Treatment Period.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 110
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part 1a (SAD): AZD4604 for inhalation via DPI(Dose 3) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 3 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 2) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 2 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 5) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 5 administered with a DPI. Part 1b: AZD4604 for oral administration AZD4604 for oral administration Healthy volunteers will receive a single PO dose of AZD4604. Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 8) AZD4604 for inhalation via DPI Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI. Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 9) AZD4604 for inhalation via DPI Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 6) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 6 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI AZD4604 for inhalation via DPI An additional cohort of healthy volunteers will receive a single inhaled dose of AZD4604 administered with a DPI. Part 1b: AZD4604 for intravenous administration AZD4604 for IV administration Healthy volunteers will receive a single IV dose of AZD4604 administered as a 20 minute infusion. Part 3 (MAD): Placebo for AZD4604 for inhalation via DPI Placebo for AZD4604 for inhalation via DPI Patients will receive placebo administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 1) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 1 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 4) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 4 administered with a DPI. Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 7) AZD4604 for inhalation via DPI Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 7 administered with a DPI. Part 1a (SAD): Placebo for AZD4604 for inhalation via DPI Placebo for AZD4604 for inhalation via DPI Healthy volunteers will receive placebo administered with a DPI. Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 9) AZD4604 for inhalation via DPI Patients will receive multiple inhaled dose of AZD4604 administered with a DPI. Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 10) AZD4604 for inhalation via DPI Patients will receive multiple inhaled dose of AZD4604 administered with a DPI. Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 10) AZD4604 for inhalation via DPI Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI. Part 2 (MAD): Placebo for AZD4604 for inhalation via DPI Placebo for AZD4604 for inhalation via DPI Healthy volunteers will receive placebo administered with a DPI. Part 3 (PoM): AZD4604 for inhalation via DPI (Dose 9 or Dose 10) AZD4604 for inhalation via DPI Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.
- Primary Outcome Measures
Name Time Method Part 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast) From Day 1 to Day 3 AUClast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Apparent total body clearance of drug from plasma after extravascular administration (CL/F) From Day 1 to Day 3 AUClast of AZD4604 following PO administration of a single dose to healthy volunteers.
Part 2: Number of healthy volunteers with AEs From screening (SAEs only) up to Final assessment (Day 13) Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 1b: Maximum observed plasma (peak) drug concentration (Cmax) From Day 1 to Day 3 Cmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Time to reach peak or maximum observed concentration or response following drug administration (tmax) From Day 1 to Day 3 tmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Time of last observed (quantifiable) concentration (tlast) From Day 1 to Day 3 tlast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 3: Number of patients with AEs From Screening (SAEs only) up to Final Assessment (Day 16) Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to patients.
Part 1a: Number of healthy volunteers with adverse events (AEs) From screening (SAEs only) up to Final assessment (Day 7) Safety and tolerability of AZD4604 following inhaled administration of single ascending doses to healthy volunteers.
Part 1b: Partial area under the plasma concentration time curve from time 0 to time 12 (AUC [0 - 12]) From Day 1 to Day 3 AUC (0 - 12) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Total body clearance of drug from plasma after intravascular administration (CL) From Day 1 to Day 3 CL of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F) From Day 1 to Day 3 Vz/F of AZD4604 following PO administration of a single dose to healthy volunteers.
Part 1b: Dose normalized AUCinf, derived by AUCinf divided by the dose administered (AUCinf/D) From Day 1 to Day 3 AUCinf/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Area under plasma concentration-time curve from zero to infinity (AUCinf) From Day 1 to Day 3 AUCinf of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Dose normalized Cmax, derived by Cmax divided by the dose administered (Cmax/D) From Day 1 to Day 3 Cmax/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz) From Day 1 to Day 3 λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz) From Day 1 to Day 3 t1/2λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Partial area under the plasma concentration time curve from time 0 to time 24 (AUC [0 - 24]) From Day 1 to Day 3 AUC (0 - 24) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1b: Volume of distribution following intravascular administration (based on terminal phase) (Vz) From Day 1 to Day 3 Vz of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Dose normalized AUClast, derived by AUClast divided by the dose administered (AUClast/D) From Day 1 to Day 3 AUClast/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
- Secondary Outcome Measures
Name Time Method Part1b: Number of healthy volunteers with AEs From screening (only SAEs) to follow-up end of treatment visit (6 ± 1 day post-dose) Safety and tolerability of AZD4604 following IV and PO administration of a single dose to healthy volunteers.
Part 1a and Part 2: tmax From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) tmax of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part1a: AUC (0 - 12) From Day 1 to Day 7 AUC (0 - 12) of AZD4604 following inhaled administration of single ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: λz From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2) λz of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: t1/2λz From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2) t1/2λz of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: AUC (0 - 24) From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2) AUC (0 - 24) of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part 2: Area under plasma concentration-time curve in the dose interval (AUCτ) From Day 1 to Day 13 AUCτ of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 1a and Part 2: Cmax From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) Cmax of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: AUClast From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) AUClast of AZD4604 following inhaled administration of single ascending doses and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a: AUCinf From Day 1 to Day 7 AUCinf of AZD4604 following administration of single ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: Cmax/D From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) Cmax/D of AZD4604 following inhaled administration of single and multiple ascending doses of AZD4604 to healthy volunteers.
Part1a: AUCinf/D From Day 1 to Day 7 AUCinf/D of AZD4604 following inhaled administration of single ascending doses of AZD4604 to healthy volunteers.
Part 2: Dose normalized AUCτ, derived by AUCτ divided by the dose administered (AUCτ/D) From Day 1 to Day 13 AUCτ/D of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 1a and Part 2: CL/F From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2) CL/F of AZD4604 following inhaled administration of single and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: Vz/F From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2) Vz/F of AZD4604 following inhaled administration of single and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: AUClast/D From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) AUClast/D of AZD4604 following inhaled administration of single and multiple ascending doses of AZD4604 to healthy volunteers.
Part 1a and Part 2: tlast From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2) tlast of AZD4604 following inhaled administration of single and multiple ascending doses of AZD4604 to healthy volunteers.
Part 2: Accumulation ratio for Cmax (Rac Cmax) On Day 7 Rac Cmax of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 2: Accumulation ratio for AUCτ (Rac AUC) On Day 7 Rac AUC of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.
Part 1b: Renal clearance of drug from plasma (CLR) From Day 1 to Day 2 CLR of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Cumulative amount of unchanged drug excreted into urine from time t1 to time t2 (Ae [t1 - t2]) From Day 1 to Day 2 Ae (t1 - t2) of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 1b: Cumulative percentage of dose excreted unchanged in urine from time t1 to time t2 (fe [t1 - t2]) From Day 1 to Day 2 Fe (t1 - t2) of AZD4604 following IV administration of a single dose to healthy volunteers.
Part 3: AUC From Days 1 to 16 AUC of AZD4604 following inhaled administration of multiple ascending doses to patients.
Part 3: Cough severity self-assessment (Visual analog scale) From Day -3 to -1, and Days 1 to 10 Effect of AZD4604 on cough severity in patients will be evaluated when compared with placebo.
Part 2: Cough severity self-assessment (Visual analog scale) Day-1 to Day 7 (Pre-dose) and Day 8 (Post -dose) Effect of AZD4604 on cough severity in healthy will be evaluated volunteers when compared with placebo.
Part 3: Cmax From Days 1 to 16 Cmax of AZD4604 following inhaled administration of multiple ascending doses to patients.
Part 3: AUCτ From Days 1 to 16 AUCτ of AZD4604 following inhaled administration of multiple ascending doses to patients.
Part 3: Change from baseline in Fractional exhaled nitric oxide (FeNO) levels From Day 1 to 10 Fractional exhaled nitric oxide (FeNO) levels will be assessed.
Trial Locations
- Locations (1)
Research Site
🇬🇧Manchester, United Kingdom