A study to evaluate the safety, tolerability and absorption to the blood after administration of single and multiple doses of AZD8154 in healthy participants.

Study identifier:D8900C00001

ClinicalTrials.gov identifier:NCT03436316

EudraCT identifier:N/A

CTIS identifier:N/A

Study Complete

Official Title

A Phase 1 Study to Assess the Safety, Tolerability and Pharmacokinetics of AZD8154 Following Single and Multiple Ascending Dose Administration in Healthy Subjects.

Medical condition

asthma

Phase

Phase 1

Healthy volunteers

Yes

Study drug

AZD8154

Sex

All

Actual Enrollment

Study type

Interventional

Age

18 Years - 45 Years

Date

Study Start Date: 26 Jul 2018

Primary Completion Date: 29 Jul 2019

Study Completion Date: 29 Jul 2019

Study design

Allocation: Randomized
Endpoint Classification: -
Intervention Model: Sequential Assignment
Masking: -
Primary Purpose: Treatment

Verification:

Verified 01 Jul 2020 by AstraZeneca

Collaborators

PAREXEL International GmbH

Inclusion and exclusion criteria

Inclusion Criteria

1. Provision of signed and dated, written informed consent before any study specific procedures.
2. Healthy male and/or female participants of non-childbearing potential aged 18 to 45 years (inclusive at the Screening Visit) with suitable veins for cannulation or
repeated venipuncture.
3. Females must have a negative pregnancy test at the Screening Visit and on admission to the Clinical Unit, must not be lactating and must be of non-child-bearing
potential, confirmed at Screening by fulfilling one of the following criteria:
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 and no more than 100 kg inclusive.
5. Subject has a FEV1 ≥ 80% of the predicted value regarding age, height, gender and ethnicity at the Screening Visit.

Exclusion Criteria

1. History of any clinically important disease or disorder which, in the opinion of the Investigator, may either put the subject at risk because of participation in the study,
or influence the results or the subject’s ability to participate in the study.
2. Subject is immuno-compromised.
3. History of diabetes, impaired fasting glucose, metabolic syndrome, hypertriglyceridemia or familial lipid disorders.
4. Current or previous history of malignancy of any kind except cutaneous basal or squamous cell carcinoma successful treated with therapy.
5. History of any respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD) or idiopathic pulmonary fibrosis (IPF).
6. Subject with latent or active tuberculosis (TB), as conformed by a positive QuantiFERON® - TB Gold test or as judged by the Investigator at the Screening Visit.
7. History or presence of GI, hepatic or renal disease or any other condition known to interfere with absorption, distribution, metabolism or excretion of drugs, or bowel
disorders not otherwise specified.
8. Any clinically important illness, medical/surgical procedure or trauma within 4 weeks of the (first) administration of the IMP.
9. Any clinically important abnormalities in clinical chemistry, hematology or urinalysis results, defined as the following:
9.1. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > the upper limit of the normal (ULN) laboratory range.
9.2. Bilirubin > 1.5 times the ULN laboratory range.
9.3. Absolute neutrophil count < lower limit of normal (LLN).
9.4. Absolute lymphocyte count < LLN.
9.5. Fasting plasma glucose > ULN.
9.6. Triglycerides > ULN.
10. Any positive result at the Screening Visit for serum hepatitis B surface antigen (HBsAg) OR hepatitis B core antibodies (anti-HBc), hepatitis C antibody and human
immunodeficiency virus (HIV).
11. Abnormal vital signs, after 5 minutes supine rest, defined as any of the following:
11.1. Systolic BP < 90 mmHg or > 140 mmHg.
11.2. Diastolic BP < 50 mmHg or > 90 mmHg.
11.3. Heart rate < 50 or > 90 beats per minute (bpm).
12. Any clinically important abnormalities in rhythm, conduction or morphology of the
12-lead safety and any clinically important abnormalities in the 12-Lead dECG as considered by the Investigator that may interfere with the interpretation of QT interval
corrected for heart rate using Fridericia’s formula (QTcF) interval changes, including abnormal ST-T-wave morphology, particularly in the CSP defined primary lead for dECG analysis or left ventricular hypertrophy.
12.1. Prolonged QTcF > 450 ms or shortened QTcF < 340 ms or family history of long QT syndrome.
12.2. PR (PQ) interval shortening < 120 ms (PR > 110 ms but < 120 ms is acceptable if there is no evidence of ventricular pre-excitation).
12.3. PR (PQ) interval prolongation (> 220 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation.
12.4. Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS >
110 ms. participants with QRS > 110 ms but < 115 ms are acceptable if there is no evidence of e.g., ventricular hypertrophy or pre-excitation.
13. Previous use of a mechanistic target of rapamycin (mTOR) antagonist (e.g., rapamycin, everolimus) or PI3K inhibitor (selective or non-selective PI3K inhibitors).
14. Known or suspected history of drug abuse as judged by the Investigator.
15. Current smokers or those who have smoked or used nicotine products (including e-cigarettes) within the previous 3 months.
16. History of alcohol abuse or excessive intake of alcohol as judged by the Investigator.
17. Positive screen for drugs of abuse or cotinine (nicotine) at the Screening Visit or admission to the Clinical Unit or positive screen for alcohol on admission to the Clinical Unit before the (first) administration of the IMP.
18. 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 AZD8154.
19. Receipt of live attenuated vaccines 2 months before (first) administration of the IMP and 3 months after the last IMP administration.
20. Excessive intake of caffeine-containing drinks or food (e.g., coffee, tea, chocolate) as judged by the Investigator.
21. Use of drugs with CYP3A enzyme inducing or inhibition properties such as St John’s Wort within 3 weeks before (first) administration of IMP.
22. Use of any prescribed or nonprescribed medication including antacids, analgesics (other than paracetamol/acetaminophen), herbal remedies, megadose vitamins (intake of 20 to 600 times the recommended daily dose) and minerals
during the 2 weeks before the (first) administration of the IMP or longer if the medication has a long half-life.
23. Plasma donation within 1 month of the Screening Visit or any blood donation/blood loss > 500 mL during the 2 months before the Screening Visit.
24. Has received another new chemical entity (defined as a compound which has not been approved for marketing) within 3 months of the (first) administration the IMP in
this study. The period of exclusion begins 3 months after the final dose or 1 month after the last visit whichever is the longest. Note: participants consented and screened, but not randomized in this study or a previous Phase 1 study, are not excluded.
25. Involvement of any Astra Zeneca or study site employee or their close relatives.
26. Judgment by the Investigator that the subject should not participate in the study if they have any ongoing or recent (i.e., during the Screening Period) minor medical
complaints that may interfere with the interpretation of study data or are considered unlikely to comply with study procedures, restrictions and requirements.
27. Participants who cannot communicate reliably with the Investigator and/or is not able to read speak and understand German language.
28. Vulnerable participants, e.g., kept in detention, protected adults under guardianship, trusteeship or committed to an institution by governmental or juridical
order.
In addition, any of the following is regarded as a criterion for exclusion from the genetic research:
29. Previous bone marrow transplant.
30. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the genetic sample collection.

This is a phase 1 study to assess the safety, tolerability and pharmacokinetics of AZD8154 following single and multiple ascending dose administration in healthy participants. This study will have 3 parts (Part 1, Part 2, and Part 3). Part 1 consists of six cohorts, each consisting of 8 participants. Depending on emerging PK and adverse event (AE) data, 1 to 2 additional inhaled dose levels, within the pre-specified dose range, may be added at the discretion of the Sponsor. One dose level cohort selected based on emerging data will be repeated using the same formulation of AZD8154 but with a larger particle size. The selected cohort (e.g., Cohort 5), referred to as the “Large Particle Size Cohort”, will be dosed at the same dose level with a larger particle size after a minimum washout period of 7 to 14 days between each dose administration. Small Particle Size Cohorts: Within each cohort, 6 participants will be randomized to receive an inhaled dose of AZD8154 (small particle size) and 2 participants will be randomized to receive inhaled placebo. Dosing for each ascending dose cohort will proceed with 2 participants in a sentinel cohort, such that 1 participant will be randomized to receive placebo and 1 participant will be randomized to receive AZD8154 (small particle size). Large Particle Size Cohort: For the selected Large Particle Size Cohort, the 6 participants that received AZD8154 (small particle size) will return for a second Treatment Period after a minimum washout period of 7 to 14 days. All 6 participants will receive an inhaled dose of AZD8154 (large particle size), at the same dose level that they received AZD8154 (small particle size) in Treatment Period 1. The duration of the washout period is based on the predicted half-life of AZD8154 and was selected to diminish the impact of carry-over effects from the first Treatment Period. Part 2: Part 2 of this study will be a single cohort. One cohort consisting of 6 participants will be enrolled into Part 2 of the study. All subjects will receive AZD8154 IV in Treatment Period 1 and then after washout, receive inhaled AZD8154 (small particle size) in Treatment Period 2. Intravenous dosing will proceed with 1 participant in a sentinel cohort, no sentinel dosing will be done in the inhaled dosing period. Part 3: Three cohorts (MAD Cohort 1 to Cohort 3), each consisting of 8 participants, will participate in Part 3 of the study. Within each cohort, 6 participants will be randomized to receive an inhaled dose of AZD8154 and 2 participants will be randomized to receive inhaled placebo. Dosing for each ascending dose cohort will proceed with 2 participants in a sentinel cohort, such that 1 participant will be randomized to receive placebo and 1 participant will be randomized to receive AZD8154. In Part 3, participants will be randomized to receive an inhaled dose of AZD8154 nebuliser suspension or placebo. Three (3) inhaled dose levels of AZD8154 that are administered once daily are planned to be investigated. Based upon emerging PK and safety data in MAD Cohorts 1 to 3, up to 2 additional inhaled dose levels, within the pre-specified dose range, may also be added at the discretion of the Sponsor.

No locations available

Arms	Assigned Interventions
Experimental: SAD Cohort 1 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 1) and 2 participants will receive placebo.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: SAD Cohort 2 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 2) and 2 participants will receive placebo.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: SAD Cohort 3 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 3) and 2 participants will receive placebo.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: SAD Cohort 4 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 4) and 2 participants will receive placebo.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: SAD Cohort 5 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 5) and 2 participants will receive placebo. Participants in this Cohort will return for a second Treatment Period after a minimum washout period of 7 to 14 days. All 6 subjects will receive an inhaled dose of AZD8154 (large particle size).	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: SAD Cohort 6 (Part 1) 6 Participants will receive AZD8154 (single inhaled small particle dose 6) and 2 participants will receive placebo.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: Cohort 1 (Part 2) All participants in this cohort will receive single IV dose of AZD8154 in Treatment Period 1 and then after washout period, will receive inhaled AZD8154 (small particle size) in Treatment Period 2.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: MAD Cohort 1 (Part 3) 6 Participants will receive AZD8154 (single inhaled dose 8) and 2 participants will receive placebo on Day 1. Participants will then receive multiple dosing of AZD8154 (inhaled dose 8) or placebo once daily from Day 4 to Day 12.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: MAD Cohort 2 (Part 3) 6 Participants will receive AZD8154 (single inhaled dose 9) and 2 participants will receive placebo on Day 1. Participants will then receive multiple dosing of AZD8154 (Inhaled dose 9) or placebo once daily from Day 4 to Day 12.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable
Experimental: MAD Cohort 3 (Part 3) 6 Participants will receive AZD8154 (single inhaled dose 10) and 2 participants will receive placebo on Day 1. Participants will then receive multiple dosing of AZD8154 (inhaled dose 10) or placebo once daily from Day 4 to Day 12.	Drug: AZD8154 SAD Part 1; 6 cohorts which receive single dosing. One cohort is invited back for large particle administration. Part 2; 1 cohort which receives IV dose and then inhaled administration of AZD8154. MAD Part 3; 3 cohorts will receive inhaled multiple dosing. Additional doses are provisional and could be adjusted based on the emerging data from the previous dose by the safety review committee (SRC). Other Name: Not applicable

Documents available

Trial Results Summaries
Available here

Contacts

Contact

AstraZeneca Clinical Study Information Center

1-877-240-9479

[email protected]

Investigators

Principal Investigator

med. Rainard Fuhr

PAREXEL Early Phase Clinical Unit Berlin