To Assess the Safety, Tolerability and Pharmacokinetics of AZD5634 Following Inhaled and Intravenous (IV)Dose Administration

NCT02679729 | Completed Phase 1 Results DMC

• 1 other identifier: D6600C00001
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 2

Brief Summary

This is a Phase 1, first-in-human (FIH) single ascending dose study being conducted to better understand the safety, tolerability and pharmacokinetics of AZD5634 in healthy subjects

Conditions

Cystic Fibrosis

Keywords

inhaled dose; intravenous dose; healthy subjects; safety; tolerability; pharmacokinetics; AZD5634; jet nebulizer

Outcome Measures

Primary Outcomes (1)

• Safety and Tolerability of AZD5634 Following Inhaled Administration of Single-ascending Doses (SAD) (Part A) and Following Administration of Single Inhaled and IV Doses (Part B).

  To assess the safety and tolerability of AZD5634 in terms of number of participants following inhaled administration of single-ascending doses (SAD) (Part A) and following administration of single inhaled and IV doses (Part B)

  Screening (serious adverse event, SAE), Day -1 (SAE), Spontaneous plus Predose, 3,12,24, and 48 h postdose (Days 1 to 3), Follow-up 7-10 days postdose, 2 months post final dose.

Secondary Outcomes (16)

• Observed Maximum Plasma Concentration, Taken Directly From the Individual Concentration-time Curve (Cmax)- For Part A and Part B

  At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)

• Area Under Concentration-time Curve From Time Zero Extrapolated to Infinity (AUC) for Part A and Part B

  At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)

• Area Under the Plasma Concentration-curve From Time Zero to Time of Last Quantifiable Concentration [AUC(0-t)] for Part A and Part B

  At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)

• Absolute Systemic Bioavailability After Inhalation (Part B Only) (Finhalation,Total)

  At predose, at 5, 15 and 30 min and at 1, 2, 3, 4, 6, 8, 12, 24, 36 and 48 h postdose (Days 1 to 3)

• Renal Clearance (CLR), Estimated by Dividing Ae(0-last) by AUC0-t - For Part A and Part B

  -12-0, 0-6, 6-12, 12-24, 24-48 h (Days 1 to 3)

Study Arms (8)

Part A, Dose Level 1

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 2

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 3

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 4

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 5

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 6

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part A, Dose Level 7

EXPERIMENTAL

Subjects will inhale single doses of AZD5634 or placebo under fasted conditions and will rinse his/her mouth with approximately 100 mL (up to 240 mL) of water which must be swallowed

Drug: AZD5634 for inhalation; Other: Placebo

Part B, Dose Level 1

EXPERIMENTAL

Subjects will receive a single dose of IV AZD5634 and after a washout period of 14 days the same subjects will receive a single dose of inhaled AZD5634

Drug: AZD5634 for infusion

Interventions

AZD5634 for inhalation DRUG

Solution, citrate buffer, saline nebulizer solution; strength 0.1 - 5 mg/g; administered by jet nebulizer

Part A, Dose Level 1; Part A, Dose Level 2; Part A, Dose Level 3; Part A, Dose Level 4; Part A, Dose Level 5; Part A, Dose Level 6; Part A, Dose Level 7

AZD5634 for infusion DRUG

Solution, citrate buffer, saline solution for infusion; strength 0.013 mg/mL

Part B, Dose Level 1

Placebo OTHER

inactive substance

Part A, Dose Level 1; Part A, Dose Level 2; Part A, Dose Level 3; Part A, Dose Level 4; Part A, Dose Level 5; Part A, Dose Level 6; Part A, Dose Level 7

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Provision of signed and dated, written informed consent prior to any study specific procedures.
• Healthy male and/or female subjects aged 18 - 50 years with suitable veins for cannulation or repeated venipuncture.
• Females must have a negative pregnancy test at screening and on admission to the unit, must not be lactating and must be of non-childbearing potential, confirmed at screening by fulfilling 1 of the following criteria:
• Post-menopausal 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 post-menopausal range.
• Documentation of irreversible surgical sterilization by hysterectomy, bilateral oophorectomy or bilateral salpingectomy, but not tubal ligation.
• Have a body mass index (BMI) between 18 and 30 kg/m2, inclusive, and weigh at least 50 kg and no more than 100 kg, inclusive.
• Have a FEV1 (Forced expiratory volume in 1 second in liters) ≥ 80% of the predicted value at screening.
• Provision of signed, written and dated informed consent for optional genetic/biomarker research.

You may not qualify if:

• History of any clinically significant 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.
• History or presence of gastrointestinal (GI), hepatic or renal disease, or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the administration of investigational medicinal product (IMP).
• Any clinically significant abnormalities in clinical chemistry, hematology, or urinalysis results, as judged by the investigator.
• Any positive result on screening for serum hepatitis B surface antigen (HBsAg), hepatitis C antibody and human immunodeficiency virus (HIV).
• Abnormal vital signs, after 10 minutes supine rest, at screening and check-in, defined as any of the following:
• Systolic blood pressure (SBP) \< 90mmHg (millimeter of mercury) or ≥ 140 mmHg
• Diastolic blood pressure (DBP) \< 50mmHg or ≥ 90 mmHg
• Heart Rate \< 45 or \> 85 beats per minute (bpm)
• Any clinically significant abnormalities in rhythm, conduction or morphology of the resting electrocardiogram (ECG) and any clinically significant abnormalities in the 12-lead ECG, as considered by the investigator that may interfere with the interpretation of QTc (QT \[ECG interval measured from the onset of the QRS complex to the end of the T wave\] interval corrected for heart rate) interval changes, including abnormal ST-T-wave morphology, particularly in the protocol defined primary lead or left ventricular hypertrophy, at screening.
• PR (PQ \[ECG interval measured from the onset of the P wave to the onset of the QRS complex\]) interval prolongation (\> 240 ms) intermittent second (Wenckebach block while asleep is not exclusive) or third degree atrioventricular (AV) block, or AV dissociation, at screening.
• Persistent or intermittent complete bundle branch block (BBB), incomplete bundle branch block (IBBB), or intraventricular conduction delay (IVCD) with QRS \> 110 ms. Subjects with QRS (ECG interval measured from the onset of the QRS complex to the J point) \> 110 ms but \< 115 ms are acceptable if there is no evidence of, for example, ventricular hypertrophy or pre-excitation, at screening.
• Serum/plasma potassium levels are outside the normal range and lower than 3.5 to 5.1 mEq/L (milliequivalents per liter) at screening and prior to dosing.
• Has active lung disease/asthma that requires treatment.
• Known or suspected history of drug abuse, as judged by the investigator.

Sponsors & Collaborators

• AstraZeneca: lead

Study Sites (2)

Research Site

Glendale, California, 91206, United States

Location

Research Site

Baltimore, Maryland, 21225, United States

Location

Related Publications (1)

• Kristensson C, Astrand A, Donaldson S, Goldwater R, Abdulai R, Patel N, Gardiner P, Tehler U, Mercier AK, Olsson M, Ersdal E, Maenpaa J, Bramer T, Malmgren A, Bennett W, Keen C. AZD5634, an inhaled ENaC inhibitor, in healthy subjects and patients with cystic fibrosis. J Cyst Fibros. 2022 Jul;21(4):684-690. doi: 10.1016/j.jcf.2022.02.010. Epub 2022 Feb 26.

  PMID: 35227647 DERIVED

MeSH Terms

Conditions

Cystic Fibrosis

Interventions

Inhalation

Condition Hierarchy (Ancestors)

Pancreatic Diseases; Digestive System Diseases; Lung Diseases; Respiratory Tract Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Infant, Newborn, Diseases

Intervention Hierarchy (Ancestors)

Respiratory Mechanics; Respiration; Respiratory Physiological Phenomena; Circulatory and Respiratory Physiological Phenomena

Results Point of Contact

• Title: Global Clinical Leader
• Organization: AstraZeneca AB

ClinicalTrialTransparency@astrazeneca.com

+46 766 346712

Study Officials

• Ronald Goldwater, MDCM, M.Sc, CPI

  PAREXEL Early Phase Clinical Unit Baltimore

  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: INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 3, 2016
• First Posted: February 10, 2016
• Study Start: February 11, 2016
• Primary Completion: October 24, 2016
• Study Completion: October 24, 2016
• Last Updated: November 5, 2018
• Results First Posted: November 5, 2018

Record last verified: 2018-03

Locations

US (2)