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

Sponsor

Aridis Pharmaceuticals, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT03669614

Collaborator

(none)

Enrollment

Locations

Arms

39.8

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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 39 subjects. Thus, the total number of subjects is 87.

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 for HV cohorts and 42 days for CF Cohorts.

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 39 adult CF. Of the 39 subjects, 30 will be randomized to receive one of the three ascending doses of AR-501, while 9 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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

87 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 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 39 adult CF subjects (10 per dose level). The first 3 subjects (sentinel subjects) in each dose level will be randomly assigned at a 2:1 ratio to receive either AR-501 or placebo, for a total of 9 CF subjects. The remaining 30 adult subjects will be randomized sequentially at a 2:3:3:2 ratio to three doses of inhaled AR-501 or placebo.This study is a dose-escalation, placebo-controlled study where subjects are randomized to receive 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 39 adult CF subjects (10 per dose level). The first 3 subjects (sentinel subjects) in each dose level will be randomly assigned at a 2:1 ratio to receive either AR-501 or placebo, for a total of 9 CF subjects. The remaining 30 adult subjects will be randomized sequentially at a 2:3:3:2 ratio to three doses of inhaled AR-501 or placebo.

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 :

Dec 7, 2018

Anticipated Primary Completion Date :

Apr 1, 2022

Anticipated Study Completion Date :

Apr 1, 2022

Arms and Interventions

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 Names: 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 Names: Control (inhaled placebo)

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 Names:

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 Names:

Control (inhaled placebo)

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

Pharmacokinetics (PK) Profile - SAD Cmax [28 days following dose administration]
Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: Observed maximum concentration (Cmax)
Pharmacokinetics (PK) Profile - SAD Tmax [28 days following dose administration]
Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: time to reach maximum concentration (Tmax)
Pharmacokinetics (PK) Profile - SAD AUC0-inf [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)
Pharmacokinetics (PK) Profile - SAD AUC0-last [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)
Pharmacokinetics (PK) Profile - SAD λz [28 days following dose administration]
Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: terminal elimination rate (λz)
Pharmacokinetics (PK) Profile - SAD t½ [28 days following dose administration]
Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: half-life (t½)
Pharmacokinetics (PK) Profile - SAD Clp [28 days following dose administration]
Pharmacokinetics Characteristics in Single Ascending Dose HV Subjects: plasma clearance (Clp)
Pharmacokinetics (PK) Profile - MAD Cmax [up to 28 days after last dose administration]
Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: Observed maximum concentration (Cmax)
Pharmacokinetics (PK) Profile - MAD Tmax [up to 28 days after last dose administration]
Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: time to reach maximum concentration (Tmax)
Pharmacokinetics (PK) Profile - MAD AUC0-inf [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)
Pharmacokinetics (PK) Profile - MAD AUC0-last [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)
Pharmacokinetics (PK) Profile - MAD λz [up to 28 days after last dose administration]
Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: terminal elimination rate (λz)
Pharmacokinetics (PK) Profile - MAD t½ [up to 28 days after last dose administration]
Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: half-life (t½)
Pharmacokinetics (PK) Profile - MAD Clp [up to 28 days after last dose administration]
Pharmacokinetics Characteristics in Multiple Ascending Dose CF Subjects: plasma clearance (Clp)

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 49 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

Inclusion Criteria (HV Subjects):

Written informed consent given by the subject.
At least ≥ 18 years old and < 50 years of age.
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.
Body mass index (BMI) between 18 and 30 kg/m2, inclusive.
Currently nonsmoking and no history of using nicotine/tobacco-containing products for ≥ 5 years prior to screening.
Normal chest X-ray, per opinion of the Investigator.
FEV1 ≥ 80% of predicted values.
No history or current illicit, pharmaceutical drug or alcohol abuse within ≤ 5 years prior to screening.
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.

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):

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

Confirmation of current colonization/infection with P. aeruginosa defined as: a positive sputum or oropharyngeal swab culture at screening.
Respiratory symptoms and CF status are stable with no acute exacerbation at the time of randomization.
BMI ≥ 18 kg/m2
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.
FEV1 ≥ 45% of predicted values.
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%).
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.

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.
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.

Female subjects who are currently pregnant or lactating.
Oral temperature above 37.5ºC at the time of screening or prior to randomization.
Clinically abnormal renal function, evidenced by serum creatinine > 1.5 mg/dL.
Need for using any nephrotoxic agents during the study.
Known allergy or hypersensitivity to albuterol.
Significantly abnormal liver function:
Total bilirubin >1.5 x upper limit of the normal range (ULN),
Alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 3 x ULN and alkaline phosphatase (ALP) > 2 x ULN
Hemoglobin <10 g/dL
Abnormal corrected serum calcium concentration prior to enrollment.
History or current use of illicit, pharmaceutical drug or alcohol abuse within 5 years prior to screening.
Positive urine screen for alcohol, cotinine and/or drugs of abuse at screening and admission.
Positive test results for Human Immunodeficiency Virus (HIV)-1/HIV-2 antibodies, Hepatitis B surface antigen (HBsAg) or Hepatitis C virus antibody (HCVAb).
Inability to comply with any study requirements based on judgement of the Investigator.
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.
Participation in another clinical trial involving receipt of an investigative product within 30 days before screening.
Any other reason as determined by an Investigator.

Exclusion Criteria (CF Subjects):

None of the following criteria can be met.

Female subjects who are currently pregnant or lactating.
Oral temperature above 37.5ºC (or temporal temperature above 38.0ºC) at the time of screening or prior to randomization.
Serum creatinine > 1.5 mg/dL or known significant kidney disease.
Significantly abnormal liver function:
Total bilirubin > 1.5 x ULN range,
ALT and/or AST > 3 x ULN range and ALP > 2 x ULN range.
History of medically attended hemoptysis < 1 year (small amount of blood streaking in sputum is acceptable).
Pulmonary exacerbations within 3 months prior to randomization (defined as requiring IV antibiotics), in the hospital or at home.
Hemoglobin < 10 g/dL.
Abnormal corrected serum calcium concentration prior to randomization (normal range is typically 8.5-10.2 mg/dL).
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.
Known allergy or hypersensitivity to albuterol or any component of the study drug or placebo
Use of illicit, pharmaceutical drug or alcohol abuse within 6 months prior to screening.
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).
History of positive test result for human immunodeficiency virus (HIV) HIV-1/HIV-2 antibodies, HBsAg or chronic hepatitis C virus infection.
Inability to comply with any study requirements based on judgement of the Investigator.
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.
Participation in another clinical trial involving receipt of an investigative product within 30 days before randomization.
Suspected or confirmed acute respiratory infection (Examples: bacterial pneumonia, influenza, COVID-19).
Any other reason as determined by an Investigator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Tucson	Arizona	United States	85724
2	Research Site	Long Beach	California	United States	90806
3	Research Site	Denver	Colorado	United States	80206
4	Research Site	Gainesville	Florida	United States	32610
5	Research Site	Hollywood	Florida	United States	33021
6	Research Site	Miami	Florida	United States	33136
7	Research Site	Orlando	Florida	United States	32803
8	Research Site	Tampa	Florida	United States	33606
9	Research Site	Overland Park	Kansas	United States	66212
10	Research Site	Portland	Maine	United States	04102
11	Research Site	Baltimore	Maryland	United States	21204
12	Research Site	Detroit	Michigan	United States	48201
13	Research Site	Omaha	Nebraska	United States	68198
14	Research Site	New York	New York	United States	10532
15	Research Site	Cleveland	Ohio	United States	44106
16	Research Site	Columbus	Ohio	United States	43205
17	Research Site	Oklahoma City	Oklahoma	United States	73104
18	Research Site	Philadelphia	Pennsylvania	United States	19104
19	Research Site	Tyler	Texas	United States	75708
20	Research Site	Salt Lake City	Utah	United States	84132
21	Research Site	Seattle	Washington	United States	98195
22	Research Site	Spokane	Washington	United States	99204