None listed
Conditions
Brief summary
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). 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. In Part D (Cohort 9), COVID-19 patients will be enrolled to receive inhaled enoxaparin (or placebo) in combination with inhaled N-acetylcysteine (multiple dosing schedule), plus best supportive care treatment for COVID-19. The dose level of inhaled enoxaparin to be evaluated in Part D will be based on safety and tolerability data obtained in Part C, or placebo. Each dose of inhaled N-acetylcysteine will be 600 mg. Dosing in each cohort Part A-C will occur in a sequential manner. The decision to escalate between dose levels and proceed to the next cohort will be based on a review of the available safety and PK data by the Safety Review Committee (SRC). The SRC will consist of (at a minimum), the PI, an independent Medical Monitor and a Sponsor’s medical representative. Other individuals (e.g. medical experts) may be invited to participate at the discretion of the SRC.
Interventions
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.
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 study Day 4. In Part D (Cohort 9), COVID-19 patients will be enrolled to receive inhaled enoxaparin (or placebo) in combination with inhaled N-acetylcysteine (multiple dosing schedule), plus best supportive care treatment for COVID-19. The dose level of inhaled enoxaparin to be evaluated in Part D will be based on safety and tolerability data obtained in Part C, or placebo. Each dose of inhaled N-acetylcysteine will be 600 mg. The subjects will be confined to the clinical trial unit throughout the treatment period and dosing will be witnessed by the site staff, the schedule of assessments will include safety assessments as required.
Sponsors
Atossa Genetics Aus Pty Ltd
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
18 Years to 64 Years
Healthy volunteers
Yes
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-vaginal intercourse between signing consent, during the study, and at least 30 days after the last dose of study therapy 10. Male volunteers must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use a condom in addition to having the female partner use a highly effective contraceptive method between signing consent, during the study, and at least 90 days after the last dose of study therapy. 11. Willingness to cooperate with the researcher and comply with all study requirements. 12. Have suitable venous access for blood sampling. Part D 1. Hospitalised males or non-pregnant, non-lactating females greater than or equal to 18 years of age at the screening visit with SARS-CoV-2 infection that is documented by an authorised diagnostic RT-PCR test (a) at or within 72 hours of screening or (b) on Day 1, prior to dose administration. 2. Must meet the NIH COVID-19 definition of moderate illness (“Individuals who have evidence of lower respiratory disease by clinical assessment or imaging and a saturation of oxygen (SpO2) greater than or equal to 94% on room air at sea level).” 3. Negative drug and alcohol tests at screening and on Day 1, prior to first dose administration (excludes cotinine). Exceptions may be made for prescribed concomitant medications, at the discretion of the Investigator. 4. 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 an FSH level > 40 IU/L at screening), 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-vaginal intercourse between signing consent, during the study, and at least 30 days after the last dose of study therapy. 5. Male volunteers must agree not to donate sperm and if engaging in sexual intercourse with a female partner who could become pregnant, must agree to use a condom in addition to having the female partner use a highly effective contraceptive method between signing consent, during the study, and at least 90 days after the last dose of study therapy. 6. The patient or a legally authorised representative has provided written informed consent. 7. The patient or the authorised representative is aware of the investigational nature of this study and willing to comply with protocol treatments, blood tests, and other evaluations listed in the informed consent form (ICF).
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. 11. History of an allergic reaction or hypersensitivity to the study drug or any component of the study drug formulation. 12. Current use of anti-inflammatory treatments o Exceptions: Steroids (e.g. complement inhibitor, anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) antibody, anti-interleukin [IL]-6 antibody) and non-steroidal anti-inflammatory drugs (NSAIDs) are allowed. o Additional exceptions: Antibiotics and some antiviral drugs (remdesivir, azithromycin) are allowed; Systemic corticosteroids are allowed. 13. Females who are currently breastfeeding. 14. Positive pregnancy test for WOCBP at screening or on Day 1, prior to dose administration. 15. Positive testing for active HIV, HBsAg or HCV antibodies at screening. 16. Presence of any uncontrolled concomitant illness, serious illness, medical conditions, or other medical history, including laboratory results, which, in the Investigator’s opinion, would be likely to interfere with their participation in the study. 17. Major surgical procedure, open biopsy, within 4 weeks prior to Screening, anticipation of need for major surgical procedure during the course of the study. 18. Any other condition or prior therapy, which, in the opinion of the Investigator, would make the patient 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.
Outcome results
None listed