Study to evaluate the safety, tolerability, and efficacy of enoxaparin for inhalation alone and in combination with N-acetylcysteine in healthy volunteers and hospitalised COVID-19 patients

• Register: ANZCTR
• Last refreshed on: 9 January 2023
• Main ID: ACTRN12621000704897
• Date of registration: 08/06/2021
• Prospective Registration: Yes
• Primary sponsor: Atossa Genetics Aus Pty Ltd
• Public title: Study to evaluate the safety, tolerability, and efficacy of enoxaparin for inhalation alone and in combination with N-acetylcysteine in healthy volunteers and hospitalised COVID-19 patients
• Scientific title: A four-part study to evaluate the safety, tolerability, and efficacy of enoxaparin for inhalation, alone and in combination with N-acetylcysteine in healthy volunteers and hospitalised COVID-19 patients
• Date of first enrolment: 30/09/2021
• Target sample size: 60
• Recruitment status: Stopped early
• URL: https://anzctr.org.au/ACTRN12621000704897.aspx
• Study type: Interventional
• Study design: Purpose: Treatment; Allocation: Randomised controlled trial; Masking: Blinded (masking used);Assignment: Parallel;Type of endpoint: Safety/efficacy;
• Phase: Phase 1 / Phase 2

Countries of recruitment

Australia, United States of America

Contacts

• Name: Dr B. Heather Fraser, PhD

• Name: Dr Steven C Quay, MD, PhD, FACS

Key inclusion & exclusion criteria

Inclusion criteria: Part A, B & C
1. Volunteers must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects.
2. Adult males and females, 18 to 64 years of age (inclusive) at the screening visit.
3. Be non-smokers (including tobacco, e-cigarettes and marijuana) for a minimum of 3 months prior to participation in the study. Non-smokers with a significant history of smoking (> 5 pack years) are not eligible.
4. Have no history or presence of tuberculosis, asthma, chronic obstructive pulmonary disease or major pulmonary airway disease (participants with history of childhood asthma but no subsequent episodes are eligible).
5. Body Mass Index (BMI) within the range of 18.5 to 30.0 kg/m2 inclusive at the screening visit, and on Day -1, prior to dosing.
6. Medically healthy without clinically significant abnormalities at the screening visit and Day -1, including:
a. Physical examination without any clinically relevant findings.
b. Systolic blood pressure in the range of 90 to 160 mm Hg (inclusive) and diastolic
blood pressure in the range of 50 to 95 mm Hg (inclusive) after 5 minutes in
supine position.
c. Heart rate in the range of 45 to 100 beats/min (inclusive) after 5 minutes rest in
supine position at the screening visit.
d. Body temperature, between 35.5°C and 37.7°C (inclusive).
e. The screening 12-lead electrocardiogram (ECG) must be within normal range
corrected QT interval [QTc] males less than or equal to 450 msec; females less than or equal to 470 msec) or with
abnormalities, which are deemed not clinically significant according to the opinion
of the Investigator at the screening visit.
f. No clinically relevant findings in serum chemistry, haematology, coagulation and
urinalysis examinations as judged by the Investigator at screening.
g. Pulmonary assessments must be within the normal range at the screening visit
and on Day -1, prior to dosing (forced expiratory volume in 1 second [FEV1], forced
vital capacity [FVC] and FEV1/FVC ratio greater than or equal to 80% of normal values; forced expiratory
flow over the middle one half of the FVC [FEF25-75%] > 75% of predicted;
h. oxygen saturation monitor greater than or equal to 95%).
7. Normal chest x-ray indicating no significant anomaly at the screening visit.
8. Negative cotinine, drug and alcohol tests at screening and Day -1.
9. Female volunteers must:
a. Be of non-child-bearing potential i.e. surgically sterilised (hysterectomy, bilateral
salpingectomy, bilateral oophorectomy at least 6 weeks before the screening visit) or
postmenopausal (where postmenopausal is defined as no menses for 12 months
without an alternative medical cause and a follicle-stimulating hormone level > 40
IU/L at the screening visit), or
b. If of childbearing potential, must have a negative pregnancy test at Screening and before the first study drug administration (Day -1). They must agree not to attempt to become pregnant must not donate ova, and must agree to use 2 forms of a highly effective contraceptive method
for penile-
Exclusion criteria: Part A, B & C
1. History or presence of significant cardiovascular, hepatic, renal, haematological, gastrointestinal, endocrine, immunologic, dermatologic, neurological or psychiatric disease, including any acute illness or surgery within the past three months determined by the Investigator to be clinically relevant.
2. History or presence of obstructive pneumonia, severe pulmonary interstitial fibrosis, alveolar proteinosis and allergic alveolitis caused by lung tumour.
3. Any history or presence of:
a. Coagulation abnormalities
b. Significant bleeding disorder
4. Known allergy to low molecular weight heparin (LMWH) or heparin, or heparin-induced thrombocytopenia.
5. Positive heparin-induced thrombocytopenia Platelet Factor 4 (PF4) antibody test at the screening visit.
6. Known allergy or sensitivity to N-acetylcysteine (NAC)(Part C only).
7. Females who are currently breastfeeding.
8. Positive serum pregnancy test for women of child-bearing potential at the screening visit or positive urine pregnancy test with confirmatory serum pregnancy test on Day -1.
9. Liver function test results (i.e., aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma-glutamyl transferase [GGT]) and total bilirubin elevated >1.2 fold above the normal limits at the screening visit.
10. Positive testing for active human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV) antibodies at the screening visit.
11. Positive testing for SARS-CoV-2 viral RNA prior to check-in on Day -1 (the test should be performed between Day -3 and Day -2, with the results to be reviewed by the PI prior to check-in.
12. Donation of blood or plasma within 30 days prior to randomisation, or loss of whole blood of more than 500 mL within 30 days prior to randomisation, or receipt of a blood transfusion within 1 year of study enrolment.
13. Participation in another investigational clinical trial within 30 days or 5 half-lives (whichever is longer) prior to the first drug administration.
14. Any other condition or prior therapy, which, in the opinion of the Investigator, would make the volunteer unsuitable for this study, including unable to cooperate fully with the requirements of the study protocol or likely to be non-compliant with any study requirements.

Part D
1. Participation in any other clinical trial of an experimental treatment for COVID-19, with the exception of emergency access treatments.
2. Concurrent treatment with other agents with actual or possible direct acting antiviral activity against SARS-CoV-2 < 24 hours prior to study drug dosing except for remdesivir and azithromycin..
3. Uncontrolled hypertension (systolic blood pressure (BP) > 150 mm Hg and/or diastolic BP > 100 mmHg), unstable angina, congestive heart failure (CHF) of any New York Heart Association (NYHA) classification, serious cardiac arrhythmia requiring treatment (exceptions: atrial fibrillation, paroxysmal supraventricular tachycardia), history of myocardial infarction within 12 months of enrolment.
4. Hypotension requiring vasoactive peptides, such as dopamine, norepinephrine, epinephrine, or dobutamine.
5. Renal function impairment with Creatinine >2 mg/dL.
6. Liver function impairment with Bilirubin >2 mg/dL.
7. Platelet count <50,000/µL.
8. Multi-organ failure.
9. Documented active infection with a bacterial pathogen requiring parenteral systemic antibiotics.
10. Bacterial or fungal sepsis.

Age minimum: 18 Years
Age maximum: 64 Years
Gender: Both males and females

Health Condition(s) or Problem(s) studied

Infection - Other infectious diseases

Respiratory - Other respiratory disorders / diseases

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ;COVID-19;
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
COVID-19

Intervention(s)

This is a Phase I/IIa, double-blind, placebo-controlled study which is subdivided into 4 parts. Parts A-C will be conducted in healthy adult participants and Part D will be conducted in hospitalised COVID-19 patients with moderate illness.
Part A (Cohorts 1-4) will be conducted as a single ascending dose (SAD) study, whereby healthy volunteers will be enrolled to receive a single dose of inhaled enoxaparin (or placebo). Three dose levels of inhaled enoxaparin will be explored in Part A (0.25, 0.5, 1 or 2 mg/kg/dose). Sentinel dosing will be employed for all dose level cohorts for Part A.

Part B (Cohorts 5-6) will be conducted as a multiple ascending dose (MAD) study, whereby healthy volunteers will be enrolled to receive multiple doses of inhaled enoxaparin (or placebo) every 12 hours (q12h) for 7 days. Two dose levels of inhaled enoxaparin will be explored in Part B (0.5 or 1 mg/kg/dose).

In Part C (Cohorts 7-8), healthy volunteers will be enrolled to receive MADs of inhaled enoxaparin (or placebo) in combination with fixed doses of inhaled N-acetylcysteine. Two dose levels of inhaled enoxaparin will be explored in Part C (0.5 or 1 mg/kg/dose). Each dose of inhaled N-acetylcysteine will be 600 mg.Sentinel dosing will be employed for all dose level cohorts for Part C.
Dosing in part C is as follows:
• Participants will receive a single dose of inhaled N-acetylcysteine on study Day 1.
• Participants will receive a single dose of inhaled enoxaparin (or placebo) on study Day 2.
• Participants will receive a single dose each of inhaled enoxaparin (or placebo) and inhaled N-acetylcysteine on study Day 3.
• Participants will receive inhaled enoxaparin (or placebo) q12h plus inhaled N-acetylcysteine every 6 hours (q6h) for 7 days starting on s

Primary Outcome(s)

Part C
• To evaluate the safety and tolerability of inhaled enoxaparin administered in healthy volunteers using a multiple dose schedule in combination with inhaled N-acetylcysteine (NAC) treatment.[Part C
Safety and tolerability endpoints/outcome assessments include:
• Incidence, type and severity of AEs
• Changes from baseline in vital sign measurements
• Changes from baseline in clinical laboratory parameters (Hematology, Coagulation, Biochemistry and Urinalysis)
• Changes from baseline in electrocardiogram (ECG) parameters
• Changes from baseline in physical examination findings including auscultation
• Changes from baseline in oxygen saturation(SpO2)
• Changes from baseline in lung spirometry

Part C outcomes will be measured at the following timepoints: Baseline, Day 1,2,3,4,5,6,7,8,9,10,11, Day 12-16, Day 17. ]

Part D
•To evaluate the safety and tolerability of inhaled enoxaparin when administered as an adjunct to inhaled N-acetylcysteine therapy in COVID-19 patients with moderate illness.[Part D
Safety and tolerability endpoints/outcome assessments include:
• Incidence, type and severity of AEs
• Changes from baseline in vital sign measurements
• Changes from baseline in clinical laboratory parameters (Hematology, Coagulation, Biochemistry and Urinalysis)
• Changes from baseline in electrocardiogram (ECG) parameters
• Changes from baseline in physical examination findings including auscultation
• Changes from baseline in oxygen saturation
• Changes from baseline in lung spirometry


Part D outcomes will be measured at the following timepoints: Baseline, Day 1,2,3,4,5,6,7,8, Day 9-14, Day 15, Days 16-28,Day 29. ]

Part A &B
•To evaluate the safety and tolerability of enoxaparin administered via inhalation (IH) using a single and multiple ascending dose schedule in healthy adult volunteers.
[Part A & B
Safety and tolerability endpoints/outcome assessments include:
•Incidence, type and severity of AEs
•Changes from baseline in vital sign measurements
•Changes from baseline in clinical laboratory parameters (Hematology, Coagulation, Biochemistry and Urinalysis)
•Changes from baseline in electrocardiogram (ECG) parameters
•Changes from baseline in physical examination findings including auscultation
•Changes from baseline in oxygen saturation (SpO2)
•Changes from baseline in lung spirometry

Part A outcomes will be measured at the following timepoints: Baseline, Day 1,2, Day 3-7, Day 8.
Part B outcomes will be measured at the following timepoints: Baseline, Day 1,2,3,4,5,6,7 Day 8-13, Day 14.
]

Secondary Outcome(s)

To assess the incidence and severity of bronchospasm associated with inhaled enoxaparin administered with inhaled N-acetylcysteine, using a combination treatment schedule in COVID-19 patients with moderate illness.(Part D). Assessed by clinical observation of breathing difficulty (including wheezing), with RR > 30/min.[ Incidence and severity of bronchospasms observed for a period of 24 hours following each dose of study drug.]

To assess the incidence and severity of local irritation associated with multiple ascending doses of inhaled enoxaparin administered in combination with inhaled N-acetylcysteine treatment in healthy volunteers (Part C). Assessed by clinical examination and participant self-report.[Incidence and severity of local irritation observed for a period of 24 hours following each dose of study drug.]

To assess the PK of inhaled enoxaparin and inhaled N-acetylcysteine when administered alone and in combination in healthy adult volunteers.(Part C)
[Part C
• PK parameters calculated include (but are not limited to):
o Maximum observed concentration (Cmax)
o Time to Cmax (Tmax)
o Area under the concentration time curve (AUC0-t)
o Apparent terminal elimination half-life (t½)

PK assessment will occur at the following timepoints:
Day 1 (5 min, 10 min, 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr), Day 2 , Day 3 (5 min, 10 min, 15 min, 30 min, 45 min, 1 hr , 2 hr, 4 hr, 6 hr, 8 hr, 12 hr), Day 4, Day 10 ( 5 min, 10 min, 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr), Day 11]

To assess the incidence and severity of bronchospasm associated with multiple ascending doses of inhaled enoxaparin administered in combination with inhaled N-acetylcysteine treatment in healthy volunteers.(Part C). Assessed by clinical observation of breathing difficulty (including wheezing), with RR > 30/min.[Incidence and severity of bronchospasms observed for a period of 24 hours following each dose of study drug.]

To assess the incidence and severity of bronchospasm following administration of single and multiple ascending doses of inhaled enoxaparin in healthy volunteers.(Part A & B). Assessed by clinical observation of breathing difficulty (including wheezing), with RR > 30/min.[Incidence and severity of bronchospasms observed for a period of 24 hours following each dose of study drug.]

To assess the incidence and severity of local irritation associated with inhaled enoxaparin administered with inhaled N-acetylcysteine, using a combination treatment schedule in COVID-19 patients with moderate illness. (Part D) Assessed by clinical examination and participant self-report.

[Part D
Incidence and severity of local irritation observed for a period of 24 hours following each dose of study drug.

]

To assess the incidence and severity of local irritation associated with single and multiple ascending doses of IH enoxaparin administration in healthy volunteers. (Part A & B). Assessed by clinical examination and participant self-report.[Incidence and severity of local irritation observed for a period of 24 hours following each dose of study drug.]

To evaluate the efficacy of inhaled enoxaparin (at study Days 8, 15 and 29) when administered with inhaled N-acetylcysteine using a combination treatment schedule, in COVID-19 patients with moderate illness. (Part D), composite assessments include assessments include Chest X-Rays, NIAID score, SOFA score,duration of hospitalisation assessed by data-linkage to medical records.[• Efficacy endpoints/outcome assessments include:
o Changes from baseline in chest x-ray findings at Day 29 post-first intervention dose.
o Changes from baseline in National Institute of Allergy and Infectious Diseases (NIAID) assessment of breathlessness score at Day 8, Day 15 and Day 29 post-first intervention dose.
o Changes from baseline in Sequential Organ Failure Assessment (SOFA) score at Day 8, Day 15 and Day 29 post-first intervention dose.
o Number of days free of supplemental oxygen at Day 8, Day 15 and Day 29 post-first intervention dose (greater than or equal to status 5 on the NIAID 8-point ordinal scale)
o Duration of hospitalisation at Day 15 and Day 29 post-first intervention dose.
o Survival (based on all-cause mortality) at Day 29 post-first intervention dose.]

To assess the pharmacokinetics (PK) of inhaled enoxaparin administered using a single and multiple ascending dose schedule in healthy adult volunteers.(Part A & B)


[Part A,& B
• PK parameters calculated include (but are not limited to):
o Maximum observed concentration (Cmax)
o Time to Cmax (Tmax)
o Area under the concentration time curve (AUC0-t)
o Apparent terminal elimination half-life (t½)

PK assessment will occur at the following timepoints:
Part A: 5 min, 10 min, 15 min, 30 min, 45 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr
Part B: Day 1 (5 min, 10 min, 15 min, 30 min, 45 min, 1 hr,2 hr, 4 hr, 6 hr, 8 hr, 12 hr) , Day 7 ( min, 10 min, 15 min, 30 min, 45 min, 1 hr,2 hr, 4 hr, 6 hr, 8 hr, 12 hr) , Day 8]

Secondary ID(s)

AT-H201-AU-01

Source(s) of Monetary Support

Atossa Therapeutics, Inc.

Secondary Sponsor(s)

Avance Clinical Pty Ltd

Ethics review

Status: Approved
Approval date: 01/07/2021
Contact:

Bellberry Human Research Ethics Committee

Results

• Results available: Yes
• Date Posted: 06/12/2022
• Date Completed: 29/07/2022