A Clinical Trial in Healthy Volunteers and Patients With Mild Asthma to Investigate a New Medicine (AZD4604) for the Treatment of Asthma

NCT04769869 | Completed Phase 1

• 1 other identifier: D8210C00001
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 3

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.

Conditions

Asthma

Keywords

AZD4604; Placebo-controlled; Pharmacokinetics; First in Human; Single Ascending Dose; Multiple Ascending Dose; Inhaled Janus Kinase (JAK) Inhibitor

Outcome Measures

Primary Outcomes (19)

• Part 1a: Number of healthy volunteers with adverse events (AEs)

  Safety and tolerability of AZD4604 following inhaled administration of single ascending doses to healthy volunteers.

  From screening (SAEs only) up to Final assessment (Day 7)

• Part 2: Number of healthy volunteers with AEs

  Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to healthy volunteers.

  From screening (SAEs only) up to Final assessment (Day 13)

• Part 1b: Maximum observed plasma (peak) drug concentration (Cmax)

  Cmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Time to reach peak or maximum observed concentration or response following drug administration (tmax)

  tmax of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Terminal rate constant, estimated by log linear least squares regression of the terminal part of the concentration time curve (λz)

  λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Half life associated with terminal slope (λz) of a semi logarithmic concentration time curve (t1/2λz)

  t1/2λz of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Partial area under the plasma concentration time curve from time 0 to time 12 (AUC [0 - 12])

  AUC (0 - 12) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Partial area under the plasma concentration time curve from time 0 to time 24 (AUC [0 - 24])

  AUC (0 - 24) of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Area under the plasma concentration curve from zero to the last quantifiable concentration (AUClast)

  AUClast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Apparent total body clearance of drug from plasma after extravascular administration (CL/F)

  AUClast of AZD4604 following PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Total body clearance of drug from plasma after intravascular administration (CL)

  CL of AZD4604 following IV administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Volume of distribution (apparent) at steady state following extravascular administration (based on terminal phase) (Vz/F)

  Vz/F of AZD4604 following PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Volume of distribution following intravascular administration (based on terminal phase) (Vz)

  Vz of AZD4604 following IV administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Dose normalized AUClast, derived by AUClast divided by the dose administered (AUClast/D)

  AUClast/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Area under plasma concentration-time curve from zero to infinity (AUCinf)

  AUCinf of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Dose normalized AUCinf, derived by AUCinf divided by the dose administered (AUCinf/D)

  AUCinf/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Dose normalized Cmax, derived by Cmax divided by the dose administered (Cmax/D)

  Cmax/D of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 1b: Time of last observed (quantifiable) concentration (tlast)

  tlast of AZD4604 following IV and PO administration of a single dose to healthy volunteers.

  From Day 1 to Day 3

• Part 3: Number of patients with AEs

  Safety and tolerability of AZD4604 following inhaled administration of multiple ascending doses to patients.

  From Screening (SAEs only) up to Final Assessment (Day 16)

Secondary Outcomes (28)

• Part1b: Number of healthy volunteers with AEs

  From screening (only SAEs) to follow-up end of treatment visit (6 ± 1 day post-dose)

• Part 1a and Part 2: Cmax

  From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2)

• Part 1a and Part 2: tmax

  From Day 1 to Day 7 (Part 1a) and from Day 1 to Day 13 (Part 2)

• Part 1a and Part 2: λz

  From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2)

• Part 1a and Part 2: t1/2λz

  From Day 1 to Day 7 (Part 1a) and on Day 7 (Part 2)

Study Arms (19)

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 1)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 1 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 2)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 2 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI(Dose 3)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 3 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 4)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 4 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 5)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 5 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 6)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 6 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 7)

EXPERIMENTAL

Healthy volunteers will receive a single inhaled dose of AZD4604 Dose 7 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): AZD4604 for inhalation via DPI

EXPERIMENTAL

An additional cohort of healthy volunteers will receive a single inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 1a (SAD): Placebo for AZD4604 for inhalation via DPI

PLACEBO COMPARATOR

Healthy volunteers will receive placebo administered with a DPI.

Drug: Placebo for AZD4604 for inhalation via DPI

Part 1b: AZD4604 for intravenous administration

EXPERIMENTAL

Healthy volunteers will receive a single IV dose of AZD4604 administered as a 20 minute infusion.

Drug: AZD4604 for IV administration

Part 1b: AZD4604 for oral administration

EXPERIMENTAL

Healthy volunteers will receive a single PO dose of AZD4604.

Drug: AZD4604 for oral administration

Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 8)

EXPERIMENTAL

Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 9)

EXPERIMENTAL

Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 10)

EXPERIMENTAL

Healthy volunteers will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 2 (MAD): Placebo for AZD4604 for inhalation via DPI

PLACEBO COMPARATOR

Healthy volunteers will receive placebo administered with a DPI.

Drug: Placebo for AZD4604 for inhalation via DPI

Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 9)

EXPERIMENTAL

Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 3 (MAD): AZD4604 for inhalation via DPI (Dose 10)

EXPERIMENTAL

Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Part 3 (MAD): Placebo for AZD4604 for inhalation via DPI

PLACEBO COMPARATOR

Patients will receive placebo administered with a DPI.

Drug: Placebo for AZD4604 for inhalation via DPI

Part 3 (PoM): AZD4604 for inhalation via DPI (Dose 9 or Dose 10)

EXPERIMENTAL

Patients will receive multiple inhaled dose of AZD4604 administered with a DPI.

Drug: AZD4604 for inhalation via DPI

Interventions

AZD4604 for inhalation via DPI DRUG

Healthy volunteers will receive AZD4604 administered with a DPI. The dose is expected to be administered between 10 to 45 minutes, depending upon dose. The dose will be administered after an overnight fast of at least 10 hours. Healthy volunteers will be allowed to drink water to prevent dehydration until 1 hour before dosing.

Part 1a (SAD): AZD4604 for inhalation via DPI; Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 1); Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 2); Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 4); Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 5); Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 6); Part 1a (SAD): AZD4604 for inhalation via DPI (Dose 7); Part 1a (SAD): AZD4604 for inhalation via DPI(Dose 3); Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 10); Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 8); Part 2 (MAD): AZD4604 for inhalation via DPI (Dose 9)

Placebo for AZD4604 for inhalation via DPI DRUG

Part 1a: An additional cohort of healthy volunteers will receive a placebo administered with a DPI. Part 2: Healthy volunteers will receive placebo administered with a DPI. They will receive BID doses on Day 1 to Day 6, and a single dose will be administered on Day 7. Part 3: Patients will receive placebo administered with a DPI. They will receive BID doses on Day 1 to Day 9, and a single dose will be administered on Day 10.

Part 1a (SAD): Placebo for AZD4604 for inhalation via DPI; Part 2 (MAD): Placebo for AZD4604 for inhalation via DPI; Part 3 (MAD): Placebo for AZD4604 for inhalation via DPI

AZD4604 for IV administration DRUG

Healthy volunteers will receive a single IV dose of AZD4604 administered over 20 minutes. The dose will be administered after an overnight fast of at least 10 hours. Healthy volunteers will be allowed to drink water to prevent dehydration until 1 hour before dosing.

Part 1b: AZD4604 for intravenous administration

AZD4604 for oral administration DRUG

Healthy volunteers will receive a single PO dose of AZD4604. The dose will be administered after an overnight fast of at least 10 hours. Healthy volunteers will be allowed to drink water to prevent dehydration until 1 hour before dosing.

Part 1b: AZD4604 for oral administration

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• All Study Parts:
• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Female subjects must have a negative pregnancy test at the Screening Visit and on admission to the Study Center or prior to randomization for Part 3 (Day -1 or Day 1 visit) and must not be lactating. Women of non-childbearing potential, must fulfill one of the following criteria:
• Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle stimulating hormone levels in the postmenopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not bilateral tubal ligation.
• Male subjects and their Women of childbearing potential (WOCBP) partners should be willing to use highly effective contraception measures and should refrain from donating sperm or fathering a child from the first day of dosing until 3 months after the last dose of investigational medicinal product (IMP).
• WOCBP must be willing to use highly effective contraception measures from the first day of dosing until at least 1 month after the last dose of IMP, such as measures that results in low failure rate, ie, less than 1% per year.
• Part 1a, Part 1b, and Part 2 Only:
• Healthy male and female (including WOCBP) volunteers aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture.
• Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 60 kg.
• Part 1a and Part 2 Only:
• \- Healthy volunteers must have a FEV1 ≥ 80% of the predicted value regarding age, height, gender and ethnicity at the Screening and the Randomization Visits in accordance with American Thoracic Society (ATS)/ European Respiratory Society (ERS) criteria.
• Part 3 Only:
• Male and female (including WOCBP) patients with mild asthma aged 18 to 65 years with suitable veins for cannulation or repeated venipuncture.
• Have a BMI between 18 and 35 kg/m2 inclusive and weigh at least 60 kg.

You may not qualify if:

• All Study Parts:
• History of any clinically important disease or disorder.
• Subject has an increased risk of infection.
• History of cancer within the last 10 years except for basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix treated and considered cured.
• Disease history suggesting abnormal immune function.
• Have received any vaccine in the 30 days prior to the first dose.
• Has a body temperature of \> 37.7°C on Day-1.
• History or presence of gastrointestinal, hepatic or renal disease.
• Any clinically important illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of Investigational medicinal product (IMP).
• High-sensitivity C-reactive protein \> upper limit of normal (ULN) at Screening Visit and on Day -1.
• Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results. Consider appropriate ethnicity adjusted local reference ranges for hematology measurements, when available.
• Abnormal vital signs at the Screening Visit, after 5 minutes supine rest.
• Known or suspected history of drug abuse.
• Current smokers or those who have smoked or used nicotine products.
• History of alcohol abuse or excessive intake of alcohol.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (3)

Research Site

Belfast, BT9 6AD, United Kingdom

Location

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

Research Site

Manchester, M23 9QZ, United Kingdom

Location

MeSH Terms

Conditions

Asthma

Interventions

Organization and Administration; Administration, Oral

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases

Intervention Hierarchy (Ancestors)

Health Services Administration; Drug Administration Routes; Drug Therapy; Therapeutics

Study Officials

• Dr Pablo Forte Soto

  Parexel Early Phase Clinical Unit (London)

  PRINCIPAL INVESTIGATOR

• Rajkumar Chetty, Dr

  Celerion

  PRINCIPAL INVESTIGATOR

• Dave Singh

  Medicines Evaluation Unit

  PRINCIPAL INVESTIGATOR

• Jorg Taubel

  Richmond Pharmacology Limited

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Masking Details: Part 1a: Healthy volunteers will be blinded to treatment allocation (single-blind design) to minimize bias. Part 1b: This part of the study is open-label and blinding is not applicable. Part 2: Healthy volunteers will be blinded to treatment allocation (single-blind design) to minimize bias. Part 3: Patients will be blinded to treatment allocation (single-blind design) to minimize bias
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 12, 2021
• First Posted: February 25, 2021
• Study Start: July 8, 2022
• Primary Completion: January 24, 2023
• Study Completion: January 24, 2023
• Last Updated: March 20, 2023

Record last verified: 2023-03

Data Sharing

• IPD Sharing: Will share
• Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please re-refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Locations

GB (3)