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

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ClinicalTrials.gov Identifier: NCT03669614
Recruitment Status : Recruiting
First Posted : September 13, 2018
Last Update Posted : April 22, 2021
Sponsor:
Information provided by (Responsible Party):
Aridis Pharmaceuticals, Inc.

Brief Summary:
This is a Phase 1/2a randomized, double-blind, two-part, dose-ascending, multicenter study of AR-501 (gallium citrate) solution, administered via inhalation, in healthy adult and P. aeruginosa infected cystic fibrosis (CF) subjects. Phase 1 of the study in HV subjects will consist of a single-ascending-dose (SAD) cohort, followed by the HV multiple-ascending-dose (MAD) cohort. Phase 2a of the study in CF subjects will consist of a MAD study design. The study will evaluate the safety and pharmacokinetic (PK) profile of single and repeat administrations of inhaled AR-501 solution in healthy adults, and the safety, PK and efficacy of repeat administrations of inhaled AR-501 solution in P. aeruginosa infected CF subjects.

Condition or disease Intervention/treatment Phase
Cystic Fibrosis Drug: Inhaled AR-501 Drug: Inhaled Placebo Phase 1 Phase 2

Detailed Description:

Three dose levels (low, medium and high) will be assessed in succession, first in healthy volunteer (HV) subjects, then in cystic fibrosis (CF) subjects. The study will be performed in 2 parts: Phase 1 part of the study in HV subjects will consist of a single-ascending-dose (SAD) cohort, followed by the HV multiple-ascending-dose (MAD) cohort. Phase 2a part of the study in CF subjects will consist of a MAD study design.

The HV cohort will include up to 48 subjects. The CF cohort will have 42 subjects. Thus, the total number of subjects is 90.

The Phase 1 HV study will be performed at a Phase 1 Clinical Study Unit and the Phase 2a will be performed at approximately 24 clinical trial sites located in the United States and possibly in Europe, some of which may be part of the Cystic Fibrosis Foundation (CFF)-accredited Therapeutic Development Network (TDN) or the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN). Subjects who meet all eligibility criteria, including giving informed consent, will be enrolled and undergo a screening period of 28 days.

The HV cohort will include up to 24 adult subjects in 3 dose groups (8 per dose group [Low, Medium and High]) for the SAD phase of the study. In each dose group, subjects will be randomly assigned in a 3:1 ratio to the active drug or placebo, resulting in 6 subjects receiving inhaled AR-501 and 2 receiving inhaled placebo in a double-blind manner. The HV MAD phase of the study will include 24 adult subjects in 3 dose groups (8 per dose group [Low, Medium and High]). In each dose group, subjects will be randomly assigned in a 3:1 ratio to active study drug or placebo, resulting in 6 subjects receiving inhaled AR-501 and 2 receiving inhaled placebo in a double-blind manner. All subjects in HV MAD cohorts will receive once weekly inhaled study drug (either AR-501 or matching placebo) for 4 weeks for a total of 5 doses.

The CF MAD cohort will evaluate 3 different dose levels for a total of 42 adult CF. Of the 42 subjects, 30 will be randomized to receive one of the three ascending doses of AR-501, while 12 will be randomized to receive placebo. All subjects in CF cohorts will receive once weekly inhaled study drug (either AR-501 or matching placebo) for 2 weeks for a total of 3 doses.

The primary purpose of this study is to assess preliminary clinical safety of inhaled AR-501. The true frequency of AEs is unknown, and the sample size cannot be estimated accurately. For unknown AEs, the probabilities of observing at least 1 AE among 36 total healthy adult subjects and 30 adult CF subjects receiving any AR-501 dose are ≥ 80% if the true rate of such events are at least 4.4% and 4.8% respectively.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:

This study is a dose-escalation, placebo-controlled study where subjects are randomized to receive either study drug or placebo.

SAD Phase:

The HV cohort will include up to 24 adult subjects in 3 groups (8 per dose group). In each dose group, subjects will be randomly assigned in a 3:1 ratio to receive a single administration of active drug (6 HVs) or placebo (2 HVs).

MAD Phase:

The HV cohort will include 24 adult HVs in 3 dose groups (8 per dose group). In each dose group, subjects will be randomly assigned in a 3:1 ratio to active drug (6 HVs) or placebo (2 HVs).

The CF MAD will evaluate 3 different dose levels in a total of 42 adult CF subjects (10 per dose level). The first 6 subjects (sentinel subjects) in each dose level will be randomly assigned at a 2:1 ratio to receive either AR-501 or placebo for three weeks. The remaining 24 adult CF subjects will be randomized at a 1:1:1:1 ratio to sequentially three doses of inhaled AR-501 or placebo for a total of 3 weekly doses.

Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: This is a standard double-blind randomized controlled trial.
Primary Purpose: Treatment
Official Title: A Phase 1/2a Randomized, Double-Blind, Two-Part, Dose-Ascending, Multicenter Study of the Safety and PK of AR-501 (Gallium Citrate), Administered Via Inhalation, in Healthy Adult and P. Aeruginosa Infected Cystic Fibrosis Subjects
Actual Study Start Date : December 7, 2018
Estimated Primary Completion Date : April 2022
Estimated Study Completion Date : April 2022


Arm Intervention/treatment
Experimental: AR-501 inhaled
Three doses (low, medium, high) of inhaled AR-501 will be used.
Drug: Inhaled AR-501
single and multiple ascending doses of inhaled AR-501
Other Name: Inhaled Gallium Citrate

Placebo Comparator: inhaled AR-501 Placebo
Three doses (low, medium, high) of inhaled placebo will be used
Drug: Inhaled Placebo
single and multiple ascending doses of inhaled placebo
Other Name: Control (inhaled placebo)




Primary Outcome Measures :
  1. Clinical safety profile (adverse events) - Single Ascending Dose [ Time Frame: 28 days following dose administration ]
    Evaluation of adverse events in HV subjects

  2. Clinical safety profile (adverse events) - Multiple Ascending Dose [ Time Frame: up to 28 days after last dose administration ]
    Evaluation of adverse events in HV and CF subjects


Secondary Outcome Measures :
  1. Pharmacokinetics (PK) Profile - SAD Cmax [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Observed maximum concentration (Cmax)

  2. Pharmacokinetics (PK) Profile - SAD Tmax [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: time to reach maximum concentration (Tmax)

  3. Pharmacokinetics (PK) Profile - SAD AUC0-inf [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: area under the time-concentration curve (AUC) from time zero to infinity (AUC0-inf)

  4. Pharmacokinetics (PK) Profile - SAD AUC0-last [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: area under the time-concentration curve (AUC) from time zero to the last dose (AUC0-last)

  5. Pharmacokinetics (PK) Profile - SAD λz [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: terminal elimination rate (λz)

  6. Pharmacokinetics (PK) Profile - SAD t½ [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: half-life (t½)

  7. Pharmacokinetics (PK) Profile - SAD Clp [ Time Frame: 28 days following dose administration ]
    Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: plasma clearance (Clp)

  8. Pharmacokinetics (PK) Profile - MAD Cmax [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: Observed maximum concentration (Cmax)

  9. Pharmacokinetics (PK) Profile - MAD Tmax [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: time to reach maximum concentration (Tmax)

  10. Pharmacokinetics (PK) Profile - MAD AUC0-inf [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: area under the time-concentration curve (AUC) from time zero to infinity (AUC0-inf)

  11. Pharmacokinetics (PK) Profile - MAD AUC0-last [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: area under the time-concentration curve (AUC) from time zero to the last dose (AUC0-last)

  12. Pharmacokinetics (PK) Profile - MAD λz [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: terminal elimination rate (λz)

  13. Pharmacokinetics (PK) Profile - MAD t½ [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: half-life (t½)

  14. Pharmacokinetics (PK) Profile - MAD Clp [ Time Frame: up to 28 days after last dose administration ]
    Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: plasma clearance (Clp)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 49 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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 prior and current colonization/infection with P. aeruginosa defined as:

    at least 2 positive cultures for PA in the last 12 months and a positive culture at screening.

  5. Respiratory symptoms and CF status are stable with no acute exacerbation at the time of randomization.
  6. Subject either using 1 alternating monthly suppressive inhaled antimicrobial therapy (at the time of randomization) OR using no suppressive inhaled antimicrobial therapy.
  7. BMI between 18 and 30 kg/m2, inclusive.
  8. 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.
  9. 1st 3 sentinels subjects in each dose group must have a FEV1 ≥ 60% of predicted values. The remaining 3 sentinel subjects and expanded dosing cohort in each dose group must have a FEV1 ≥ 45% of predicted values.
  10. 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%).
  11. 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.
  12. 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.
  13. Ability to produce/expectorate sputum sample.

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 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, requiring hospitalization (small amount of blood streaking in sputum is acceptable).
  6. Pulmonary exacerbations within 3 months prior to randomization.
  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. History or current use of illicit, pharmaceutical drug or alcohol abuse within 5 years 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03669614


Contacts
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Contact: Lynne M Deans, MT 9252003089 deansl@aridispharma.com

Locations
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United States, Florida
Research Site Recruiting
Orlando, Florida, United States, 32803
United States, Kansas
Research Site Completed
Overland Park, Kansas, United States, 66212
Sponsors and Collaborators
Aridis Pharmaceuticals, Inc.
Investigators
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Study Director: Hasan S Jafri, MD, FAAP Aridis Pharmaceuticals, Inc.
Study Director: Alan H Cohen, MD Aridis Pharmaceuticals, Inc.
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Responsible Party: Aridis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03669614    
Other Study ID Numbers: AR-501-001
First Posted: September 13, 2018    Key Record Dates
Last Update Posted: April 22, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: The Sponsor has not assessed whether to make individual participant data (IPD) available to other researchers.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Aridis Pharmaceuticals, Inc.:
Cystic Fibrosis
Gallium Citrate
Pseudomonas Aeruginosa
Additional relevant MeSH terms:
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Cystic Fibrosis
Fibrosis
Pathologic Processes
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Gallium citrate
Molecular Mechanisms of Pharmacological Action
Radiopharmaceuticals