A Study in Healthy Volunteers and Patients With Mild Asthma to Investigate the Safety, Anti-inflammatory Effect of Inhaled AZD0449

NCT03766399 | Completed Phase 1 Results

• 2 other identifiers: D5371C000012018-003469-32
• Study Type: interventional
• Target: 131
• Locations: 3 countries
• Sites: 4

Brief Summary

This will be a Phase I, first in human (FIH) study consisting of the following parts: Part 1a (SAD), Part 1b (IV Cohort), Part 2 (Multiple ascending dose (MAD), and Part 3 dry-powder inhalation (DPI)/ Proof of mechanism (PoM). Part 1a of the study will be a randomized, single-blind, placebo-controlled, SAD, sequential group design study performed at a single study center. Part 1b, will be an open-label, single-dose, single-cohort study. It will follow a 2-stage design in the way that participants from Part 1a will be selected for the IV Cohort in Part 1b. Part 2 of the study will be a randomized, single-blind, placebo-controlled, MAD, sequential group design and study performed at 3 study centers. Part 3a/b will be a randomized, single-blind, placebo-controlled, DPI/PoM study. The expected duration of each subject in Part 1a of the study is up to 36 days and up to 53 days for subjects participating in Part 1b. The expected duration of each participant in Part 2 is up to 52 days and Part 3 is up to 55 days.

Conditions

Asthma

Keywords

Inhaled JAK inhibitor

Outcome Measures

Primary Outcomes (12)

• Number of Participants With Adverse Events and Serious Adverse Events

  Safety and tolerability of AZD0449 following inhaled administration of single ascending doses to healthy participants, inhaled nebulized administration of multiple ascending doses to healthy participants and patients with mild asthma, and repeated inhaled administration to patients with mild asthma using a DPI was assessed.

  From screening up to follow-up visit [Part 1 a (6±1 Days post-dose)] [Part 2a (Day 22±1 (10±1 days post-last dose)], Safety Monitoring Period 2b/3a [Day 17 to 27 (15 day post-last dose)]

• Maximum Observed Plasma Concentration (Cmax)

  Cmax of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf)

  AUCinf of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast)

  AUClast of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC(0-24))

  AUC (0-24) of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Time to Reach Peak or Maximum Observed Concentration Following Drug Administration (Tmax)

  tmax of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Terminal Halflife, Estimated as (ln2)/-λz (t½λz )

  t½λz of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Total Body Clearance of Drug From Plasma After Intravascular Administration (CL)

  CL of AZD0449 following intravenous administration of a single dose of AZD0449 to healthy volunteers was assessed.

  Part 1b: Day 1

• Volume of Distribution for Parent Drug at Terminal Phase [Intravenous Administration] (λz)

  Vz of AZD0449 following intravenous administration of a single dose of AZD0449 to healthy volunteers was assessed.

  Part 1b: Day 1

• Terminal Rate Constant, Estimated by Loglinear Leastsquares Regression of the Terminal Part of the -Concentrationtime- Curve (λz)

  λz of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Time of Last Quantifiable Concentration (Tlast)

  tlast of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

• Dose Normalized Cmax (Cmax/D)

  Cmax/D of AZD0449 following intravenous administration of a single dose to healthy participants was assessed.

  Part 1b: Day 1

Secondary Outcomes (14)

• Number of Participants With Adverse Events and Serious Adverse Events

  From screening up to follow-up visit [Part 1b (6±1 Days post-dose)]

• Maximum Observed Plasma Concentration (Cmax)

  Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12

• Area Under the Plasma Concentration Time Curve From Time Zero to Infinity (AUCinf)

  Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12

• Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast)

  Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12

• Area Under the Plasma Concentration Time Curve From Time Zero to 24 Hours After Dosing (AUC(0-24))

  Part 1a: Day 1, Part 2 and 3: Day 1 and Day 12

Study Arms (13)

Part 1a (SAD) Cohort 1

EXPERIMENTAL

6 participants will receive inhaled dose 1 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1a (SAD) Cohort 2

EXPERIMENTAL

6 participants will receive inhaled dose 2 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1a (SAD) Cohort 3

EXPERIMENTAL

6 participants will receive inhaled dose 3 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1a (SAD) Cohort 4

EXPERIMENTAL

6 participants will receive inhaled dose 4 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1a (SAD) Cohort 5

PLACEBO COMPARATOR

6 participants will receive inhaled dose 5 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1a (SAD) Cohort 6

EXPERIMENTAL

6 participants will receive inhaled dose 6 of AZD0449 nebulized suspension and 2 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1b (IV cohort 1)

EXPERIMENTAL

All 6 participants will receive single IV dose of AZD0449 solution.

Drug: AZD0449; Drug: Placebo

Part 2a (MAD) Cohort 1

EXPERIMENTAL

6 participants will receive inhaled dose 7 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 2a (MAD) Cohort 2

EXPERIMENTAL

6 participants will receive inhaled dose 8 of AZD0449 nebulized suspension and 3 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 2b (MAD/healthy volunteers) Cohort 3

EXPERIMENTAL

18 healthy volunteers will receive inhaled dose 9 of AZD0449 nebulized suspension and 12 healthy volunteers will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 3a (DPI/PoM)

EXPERIMENTAL

18 participants will receive inhaled dose 10 of AZD0449 DPI and 6 participants will receive inhaled placebo.

Drug: AZD0449; Drug: Placebo

Part 1b (IV cohort 2)

EXPERIMENTAL

6 healthy volunteers will receive single IV dose of AZD0449 solution.

Drug: AZD0449; Drug: Placebo

Part 3b (DPI/healthy volunteers)

EXPERIMENTAL

Part 3b is optional. 8 healthy volunteers; 6 volunteers will receive AZD0449 DPI and 2 volunteers will recieve placebo.

Drug: AZD0449; Drug: Placebo

Interventions

AZD0449 DRUG

Participants will receive single inhaled AZD0449 nebulizer suspension and single IV dose of AZD0449 solution.

Part 1a (SAD) Cohort 1; Part 1a (SAD) Cohort 2; Part 1a (SAD) Cohort 3; Part 1a (SAD) Cohort 4; Part 1a (SAD) Cohort 5; Part 1a (SAD) Cohort 6; Part 1b (IV cohort 1); Part 1b (IV cohort 2); Part 2a (MAD) Cohort 1; Part 2a (MAD) Cohort 2; Part 2b (MAD/healthy volunteers) Cohort 3; Part 3a (DPI/PoM); Part 3b (DPI/healthy volunteers)

Placebo DRUG

Participants will receive single dose of placebo for AZD0449 (nebulizer suspension).

Part 1a (SAD) Cohort 1; Part 1a (SAD) Cohort 2; Part 1a (SAD) Cohort 3; Part 1a (SAD) Cohort 4; Part 1a (SAD) Cohort 5; Part 1a (SAD) Cohort 6; Part 1b (IV cohort 1); Part 1b (IV cohort 2); Part 2a (MAD) Cohort 1; Part 2a (MAD) Cohort 2; Part 2b (MAD/healthy volunteers) Cohort 3; Part 3a (DPI/PoM); Part 3b (DPI/healthy volunteers)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Part 1a/b: 1. Provision of signed and dated, written informed consent before any study specific procedures (applicable for all parts). 2. Healthy male volunteers and healthy female volunteers (for Part 1a and Part 1b first IV cohort, female volunteers must be of non-childbearing potential), aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. 3. Female patients must not be lactating and must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit. Women of non-childbearing potential must fulfill one of the following criteria (Applicable for all parts): 3.1. Postmenopausal defined as amenorrhea for at least 12 months or more following cessation of all exogenous hormonal treatments and follicle-stimulating hormone (FSH) levels in the postmenopausal range. 3.2. Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy but not tubal ligation. 4. Have a body mass index (BMI) between 18 and 30 kg/m2 inclusive and weigh at least 60 kg. 5. Healthy volunteer has a Forced Expiratory Volume in one second (FEV1) ≥80% of the predicted value regarding age, height, gender and ethnicity at the Screening Visit. 6. Male volunteers and their 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 IMP. 7. Female volunteers in Part 1b second IV cohort should be willing to use highly effective contraception measures from the first day of dosing until 1 month after the last dose of IMP. 8. Provision of signed, written and dated informed consent for optional genetic research. If a volunteer declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the volunteer. The volunteer will not be excluded from other aspects of the study described in this protocol. Patients with mild asthma (Part 2a and Part 3a): 1. Male and female (including WOCBP) patients with mild asthma aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. 2. Patients must be willing to remain in house at the study center for 16 consecutive days (part 2a) or for 30 consecutive days, optional from Day 17 for Germany (part 3a). 3. Have a BMI between 18 and 35 kg/m2 inclusive and weigh at least 50 kg. 4. Physician diagnosed (mild) asthma for at least 6 months prior to screening. 5. Lung function ≥70% predicted for Forced Expiratory Volume in 1 second (FEV1) at the Screening Visit AND at the 12 h timepoint on Day -1, in accordance with the American Thoracic Society (ATS)/European Respiratory Society (ERS) criteria. 6. Have a FeNO of ≥30 ppb at the Screening Visit and at the 12 h timepoint on Day -1. 7. Male patients and their 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 IMP (applicable for part 2b and 3b). 8. Female patients should be willing to use highly effective contraception measures from the first day of dosing until 1 month after the last dose of IMP. 9. Provision of signed, written and dated informed consent for optional genetic research. If a patient declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this protocol.
• Healthy volunteers (Part 2b and Part 3b): 1. Healthy male and female (including WOCBP) volunteers aged 18 to 55 years with suitable veins for cannulation or repeated venipuncture. 2. Have a BMI between 18 and 30 kg/m2 inclusive and weigh at least 60 kg. 3. Healthy volunteer has a Forced Expiratory Volume in one second (FEV1) ≥80% of the predicted value regarding age, height, gender and ethnicity at the Screening Visit and at the 12 h timepoint on Day -1, in accordance with the ATS/ERS criteria. 4. Female volunteers should be willing to use highly effective contraception measures from the first day of dosing until 1 month after the last dose of IMP. 5. Provision of signed, written and dated informed consent for optional genetic research. If a healthy volunteer declines to participate in the genetic component of the study, there will be no penalty or loss of benefit to the healthy volunteer. The healthy volunteer will not be excluded from other aspects of the study described in this protocol.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (4)

Research Site

Berlin, 14050, Germany

Location

Research Site

Wellington, 6021, New Zealand

Location

Research Site

Harrow, HA1 3UJ, United Kingdom

Location

Research Site

Manchester, M23 9GP, United Kingdom

Location

Related Links

• Related Info
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MeSH Terms

Conditions

Asthma

Condition Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Global Clinical Head
• Organization: AstraZeneca Clinical Study Information Center

information.center@astrazeneca.com

+1-877-240-94 79

Study Officials

• Dave Singh

  The Medicines Evaluation Unit

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 8, 2018
• First Posted: December 6, 2018
• Study Start: November 30, 2018
• Primary Completion: June 24, 2021
• Study Completion: June 24, 2021
• Last Updated: August 23, 2024
• Results First Posted: August 23, 2024

Record last verified: 2024-03

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 rerefer 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

DE (1); GB (2); NZ (1)