A Double-Blind, Active-Controlled, Multiple-Ascending Dose Study of Aerosolized RSP-1502 in Subjects With CF and Chronic PA Lung Infection

Study Overview
=================
Brief Summary
-----------------
This dose escalation study will evaluate 4 doses of RSP-1502 in sequential cohorts of 8 subjects each. In each cohort, 6 subjects will receive RSP-1502 and 2 will receive active control. Study drug (RSP-1502 or active control) will be administered by inhalation twice daily (BID) for 14 days. Planned RSP-1502 doses include 300 mg tobramycin plus ascending doses of CaEDTA (16 mg, 32 mg, 75 mg and 150 mg). Dose escalation will proceed after Safety Review Committee (SRC) review of the safety and tolerability data from the previous cohort. The SRC will determine the maximum tolerated dose (MTD) after completion of the fourth cohort. Following determination of the MTD, a fifth cohort (n = 20) will be randomized (1:1) to treatment with RSP-1502 (at the MTD) or active control administered BID for 14 days. All subjects will be followed for 14 days after completion of dosing.

Detailed Description
-----------------
All Cohorts: Screening will occur within 35 days prior to Day 1. Informed consent will be obtained prior to any study procedures being performed. Eligibility assessments will be performed during screening. Cohorts 1 to 4: Treatment Period (Day 1 to Day 14 ± 2 days) Subjects will report to the testing facility on Day 1 for confirmation of eligibility. Baseline assessments and measurements will be performed prior to dosing and study assessments on Day 1. Subjects will be released from the testing facility following dosing and study assessments on Day 1. Subjects will return to the testing facility on Days 2 and 14 for study assessments; on these days, a dose of study drug will be administered in the testing facility. Study drug dosing will continue until the Day 14 visit. Cohort 5: Treatment Period (Day 1 to Day 14 ± 2 days) Subjects will report to the testing facility on Day 1 for confirmation of eligibility. Baseline assessments and measurements will be performed prior to dosing and study assessments on Day 1. Subjects will return to the testing facility on Day 14 for study assessments; on these days, a dose of study drug will be administered in the testing facility. Study drug dosing will continue until the Day 14 visit. All Cohorts (including Cohort 5): Follow-Up Period (Day 15 to Day 28 ± 2 days): On Days 7 and 21, concomitant medications and adverse events (AEs) will be assessed via a phone call. Subjects will return to the testing facility on Day 28 for study assessments. Subjects will be discharged from the study on Day 28 after final assessments are performed.

Official Title
-----------------
A Double-Blind, Active-Controlled, Multiple-Ascending Dose, Phase 1b Study of Aerosolized RSP-1502 Delivered Via the PARI LC Plus® Nebulizer in Subjects With Cystic Fibrosis and Chronic Pseudomonas Aeruginosa Lung Infection

Conditions
-----------------
Cystic Fibrosis Lung, Respiratory Infections, Recurrent, Chronic, Pseudomonas Aeruginosa

Intervention / Treatment
-----------------
* Drug: RSP-1502
* Drug: Tobramycin inhalation solution


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Males or females aged ≥18 years of age. Diagnosis of CF based on the following: historical positive sweat chloride value ≥ 60 mEq/L, and/or genotype with two identifiable mutations consistent with CF, accompanied by one or more clinical features consistent with the CF phenotype. History of P. aeruginosa-positive sputum cultures or throat swabs with at least 50% positive in the year preceding screening. P. aeruginosa-positive sputum culture at screening. Forced expiratory volume in 1 second (FEV1) ≥ 40 and ≤ 90% predicted per Global Lung Function Initiative (GLI) equation, pre- or post-bronchodilator. Must be able to withhold all other inhaled tobramycin from Day 28 to Day 28 of study participation. Must be able to withhold all other inhaled antibiotics from Day -14 to Day 28. Medically stable with no evidence of significant new or acute respiratory symptoms within 30 days prior to screening. Hematology, clinical chemistry, and urinalysis results with no clinically significant abnormalities that would interfere with the study assessments at screening as determined by the investigator. Female subjects of childbearing potential, defined as not surgically sterile or at least 2 years postmenopausal, must agree to use one of the following forms of contraception from screening through the Day 28 visit: hormonal (oral, implant, or injection) begun > 30 days prior to screening, barrier (condom, diaphragm with spermicide), intrauterine device, or vasectomized partner (6 months minimum). Male subjects must show documentation of infertility or agree to use condoms during study participation. Must be able to communicate with site personnel and to understand and voluntarily sign the Informed Consent Form. Exclusion Criteria: A history of previous allergy or sensitivity to components of RSP 1502. A history of intolerance to inhaled tobramycin (TOBI®, BETHKIS®, TOBI® Podhaler®, tobramycin inhalation solution). eGFR < 40 mL/min, or serum bilirubin > 2X or serum transaminases > 3X the upper limit of normal range at screening. Currently taking other medications with known nephrotoxic, neurotoxic, or ototoxic potential. Currently taking ethacrynic acid, furosemide, urea, or intravenous mannitol. Lung infection with organisms associated with a more rapid decline in pulmonary status (including, but not limited to, Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus). For subjects who have had a history of a positive culture, the investigator will apply the following criteria to establish whether the subject is free of infection with such organisms: The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent. The subject has had at least 2 respiratory tract cultures negative for such organisms within the 12 months before the date of informed consent, with the first and last of these separated by at least 3 months, and the most recent one within the 6 months before the date of informed consent. Consistent inability to produce sputum and unwillingness to perform sputum induction. Any significant clinical/laboratory/radiological/spirometric sign of unstable or unexpectedly deteriorating respiratory disease within 30 days prior to the first study drug administration. Initiation or adjustment of chronic airway medications (eg, inhaled corticosteroids; chronic suppressive antibacterial treatment) or airway clearance regimen (eg, nebulized saline, rhDNase, initiation of mechanical vest or handheld airway clearance device) within 28 days prior to screening. Individuals can be rescreened 28 days after these agents/therapies have been established for at least 28 days. Is immunocompromised due to illness, or solid or hematological organ transplant. Requires systemic prednisone (or equivalent) > 10 mg daily. Smoking or vaping tobacco or any substance within 6 months prior to screening and anticipated inability to refrain from smoking throughout the study. Female subjects who are pregnant, lactating, or have a positive serum human chorionic gonadotropin (pregnancy) test, as determined by laboratory testing. Positive result on SARS-CoV-2 (COVID-19) test assessed by rapid antigen testing (RAT) at Screening or Day 1. HIV positive. Active Hepatitis B or C. History of recreational drug or alcohol use/abuse which in the opinion of the investigator will compromise the patient's ability to comply with the study protocol. Participation in a clinical study with administration of an investigational drug product within the previous 30 days, or five half-lives of the previously administered investigational product.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RSP-1502<br>Each dose of RSP-1502 includes 300 mg tobramycin and an ascending dose of CaEDTA. Cohort 1: 300 mg tobramycin + 16 mg CaEDTA Cohort 2: 300 mg tobramycin + 32 mg CaEDTA Cohort 3: 300 mg tobramycin + 75 mg CaEDTA Cohort 4: 300 mg tobramycin + 150 mg CaEDTA Cohort 5 will receive 300 mg tobramycin + CaEDTA at the MTD. | Drug: RSP-1502<br>* RSP-1502 is a sterile, preservative free solution to be administered by inhalation via a nebulizer. Each dose of RSP-1502 contains the active components tobramycin (60 mg/mL, 300 mg/vial) and CaEDTA. RSP-1502 contains Tromethamine USP (Tris), citric acid and sodium chloride as excipients. Additionally, sulfuric acid is used for pH adjustment.<br>|
| Active Comparator: Active Control<br>• Tobramycin Inhalation Solution 300 mg. | Drug: Tobramycin inhalation solution<br>* Tobramycin inhalation solution is 300 mg tobramycin in 5 mL solution.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events |  | Day 1 through Day 28 | 
| Treatment-emergent serious adverse events |  | Day 1 through Day 28 | 
| Changes in post-dose spirometry | forced expiratory volume in 1 second | Day 1, Day 2, and Day 14 | 
| Pulmonary exacerbations | a period of treatment with intravenous antibiotics in the hospital and/or at home | Day 1 through Day 28 | 
| Changes in post-dose electrocardiogram results | PR interval, QRS interval, QT interval | Day 1 and Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic parameters for CaEDTA | Peak serum concentration (Cmax) | Day 1 | 
| Pharmacokinetic parameters for CaEDTA | Exposure (area under the serum concentration versus time curve [AUC]) | Day 1 through Day 28 | 
| Pharmacokinetic parameters for CaEDTA | Time to maximum serum concentration (Tmax) | Day 1 through Day 28 | 
| Pharmacokinetic parameters for tobramycin | Peak serum concentration (Cmax) | Day 1 | 
| Pharmacokinetic parameters for tobramycin | Exposure (area under the serum concentration versus time curve [AUC]) | Day 1 through Day 28 | 
| Pharmacokinetic parameters for tobramycin | Time to maximum serum concentration (Tmax) | Day 1 |