SAD and MAD of Inhaled AR-501 in Health Adults and P. Aeruginosa Infected Cystic Fibrosis Subjects

This is an interventional treatment trial for Cystic Fibrosis focused on measuring Cystic Fibrosis, Gallium Citrate, Pseudomonas Aeruginosa Read More

Inclusion Criteria (HV Subjects):

1. Written informed consent given by the subject.
2. At least ≥ 18 years old and < 50 years of age.
3. Healthy with no acute medical condition for ≥ 2 weeks prior to screening and no known chronic medical condition requiring regular medical follow up and care.
4. Body mass index (BMI) between 18 and 30 kg/m2, inclusive.
5. Currently nonsmoking and no history of using nicotine/tobacco-containing products for ≥ 5 years prior to screening.
6. Normal chest X-ray, per opinion of the Investigator.
7. FEV1 ≥ 80% of predicted values.
8. No history or current illicit, pharmaceutical drug or alcohol abuse within ≤ 5 years prior to screening.

9. A female subject must meet one of the following criteria:

   If of childbearing potential - agrees to use one of the accepted contraceptive regimens from at least 30 days prior to the first administration of the study medication, during the study, and for at least 90 days after the last dose of the study medication. An acceptable method of contraception includes one of the following:

   • Abstinence from heterosexual intercourse
   • Hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
   • Intrauterine device (with or without hormones), OR
   • Agrees to use a double barrier method (e.g., condom and spermicide) during the study and for at least 90 days after the last dose of the study medication

   If a female of non-childbearing potential, the subject should be surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses), as confirmed by follicle stimulating hormone (FSH) levels.

10. A male subject must agree to use a double barrier method (e.g., condom and spermicide) during the study and for at least 90 days after the last dose of the study medication.

Inclusion Criteria (CF Subjects):

1. Written informed consent given by the subject.
2. At least18 years old

3. Documentation of a CF diagnosis as evidenced by one or more clinical features consistent with the CF phenotype and one or more of the following criteria:

   • Sweat chloride equal to or greater than 60 mmol/liter by quantitative pilocarpine iontophoresis test (QPIT)
   • Two well-characterized, disease-causing mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
4. Confirmation of current colonization/infection with P. aeruginosa defined as: a positive sputum or oropharyngeal swab culture at screening.
5. Respiratory symptoms and CF status are stable with no acute exacerbation at the time of randomization.
6. BMI ≥ 18 kg/m2
7. Currently non-smoking and no history of using nicotine/tobacco-containing products or smoking/vaping (inhaled tobacco products or other inhaled substances) for ≥ 1 year prior to screening.
8. FEV1 ≥ 45% of predicted values.
9. Serum creatinine and total bilirubin are both < 1.5 x upper limit of normal (ULN) range (isolated bilirubin > 1.5 x ULN range is acceptable if bilirubin is fractionated and direct bilirubin is < 35%).

10. A female subject must meet one of the following criteria:

    • If of childbearing potential - agrees to use one of the accepted contraceptive regimens from at least 21 days prior to the first administration of the study medication, during the study, and for at least 28 days after the last dose of the study medication. An acceptable method of contraception includes one of the following:

      • Abstinence from heterosexual intercourse
      • Hormonal contraceptives (birth control pills, injectable/implant/insertable hormonal birth control products, transdermal patch)
      • Intrauterine device (with or without hormones), OR
      • Agrees to use a double barrier method (e.g., condom and spermicide) during the study and for at least 28 days after the last dose of the study medication
    • If a female of non-childbearing potential, the subject should be surgically sterile (i.e., has undergone complete hysterectomy, bilateral oophorectomy, or tubal ligation) or in a menopausal state (at least 1 year without menses), as confirmed by FSH levels.
11. A male subject must agree to use a double barrier method (e.g., condom and spermicide) during the study and for at least 28 days after the last dose of the study medication.
12. Ability to produce an oropharyngeal sample (e.g., Expectorated Sputum or throat swab).

Exclusion Criteria (HV Subjects):

None of the following criteria can be met.

1. Female subjects who are currently pregnant or lactating.
2. Oral temperature above 37.5ºC at the time of screening or prior to randomization.
3. Clinically abnormal renal function, evidenced by serum creatinine > 1.5 mg/dL.
4. Need for using any nephrotoxic agents during the study.
5. Known allergy or hypersensitivity to albuterol.

6. Significantly abnormal liver function:

   1. Total bilirubin >1.5 x upper limit of the normal range (ULN),
   2. Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 x ULN and alkaline phosphatase (ALP) > 2 x ULN
7. Hemoglobin <10 g/dL
8. Abnormal corrected serum calcium concentration prior to enrollment.
9. History or current use of illicit, pharmaceutical drug or alcohol abuse within 5 years prior to screening.
10. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening and admission.
11. Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 antibodies, Hepatitis B surface antigen (HBsAg) or Hepatitis C virus antibody (HCVAb).
12. Inability to comply with any study requirements based on judgement of the Investigator.
13. Any medical, psychological, cognitive, social or legal conditions that would interfere in the ability to give an informed consent and/or participate fully in the study.
14. Participation in another clinical trial involving receipt of an investigative product within 30 days before screening.
15. Any other reason as determined by an Investigator.

Exclusion Criteria (CF Subjects):

None of the following criteria can be met.

1. Female subjects who are currently pregnant or lactating.
2. Oral temperature above 37.5ºC (or temporal temperature above 38.0ºC) at the time of screening or prior to randomization.
3. Serum creatinine > 1.5 mg/dL or known significant kidney disease.

4. Significantly abnormal liver function:

   1. Total bilirubin > 1.5 x ULN range,
   2. ALT and/or AST > 3 x ULN range and ALP > 2 x ULN range.
5. History of medically attended hemoptysis < 1 year (small amount of blood streaking in sputum is acceptable).
6. Pulmonary exacerbations within 3 months prior to randomization (defined as requiring IV antibiotics), in the hospital or at home.
7. Hemoglobin < 10 g/dL.
8. Abnormal corrected serum calcium concentration prior to randomization (normal range is typically 8.5-10.2 mg/dL).
9. Any change (initiation, change in type of drug, dose modification, schedule modification, interruption, discontinuation, or re-initiation) in a chronic treatment/prophylaxis regimen for CF or CF-related conditions within 2 weeks prior to randomization.
10. Known allergy or hypersensitivity to albuterol or any component of the study drug or placebo
11. Use of illicit, pharmaceutical drug or alcohol abuse within 6 months prior to screening.
12. Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening (positive results for a subject on Orkambi should have a confirmatory test for cannabinoids performed, e.g., reflex testing, to rule out cross reaction with Orkambi).
13. History of positive test result for human immunodeficiency virus (HIV) HIV-1/HIV-2 antibodies, HBsAg or chronic hepatitis C virus infection.
14. Inability to comply with any study requirements based on judgement of the Investigator.
15. Any medical, psychological, cognitive, social or legal conditions that would interfere in the ability to give an informed consent and/or participate fully in the study.
16. Participation in another clinical trial involving receipt of an investigative product within 30 days before randomization.
17. Suspected or confirmed acute respiratory infection (Examples: bacterial pneumonia, influenza, COVID-19).
18. Any other reason as determined by an Investigator.