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

Sponsor

Respirion Pharmaceuticals Pty Ltd (Industry)

Overall Status

Not yet recruiting

CT.gov ID

NCT06016088

Collaborator

(none)

Enrollment

Locations

Arms

16.1

Anticipated Duration (Months)

3.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Cystic Fibrosis Lung Respiratory Infections, Recurrent, Chronic Pseudomonas Aeruginosa	Drug: RSP-1502 Drug: Tobramycin inhalation solution	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

52 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

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

Anticipated Study Start Date :

Oct 1, 2023

Anticipated Primary Completion Date :

Feb 1, 2025

Anticipated Study Completion Date :

Feb 1, 2025

Arms and Interventions

Arm	Intervention/Treatment
Experimental: RSP-1502 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 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.
Active Comparator: Active Control • Tobramycin Inhalation Solution 300 mg.	Drug: Tobramycin inhalation solution Tobramycin inhalation solution is 300 mg tobramycin in 5 mL solution.

Arm

Intervention/Treatment

Experimental: RSP-1502

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

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.

Active Comparator: Active Control

• Tobramycin Inhalation Solution 300 mg.

Drug: Tobramycin inhalation solution

Tobramycin inhalation solution is 300 mg tobramycin in 5 mL solution.

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

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

Other Outcome Measures

Pharmacodynamic parameters [Day 1, Day 14, and Day 28]
Inflammatory markers in sputum
Microbiology parameters [Day 1 to Day 14; Day 1 to Day 28]
Change from baseline in Pseudomonas aeruginosa CFUs
Change from baseline in spirometry [Day 1 to Day 28]
forced expiratory volume in 1 second (absolute change; change in % predicted)
Change from baseline in CFQ-R Respiratory Symptoms Score [Day 1 to Day 28]
Change from baseline in Chronic Respiratory Infection Symptom Score [Day 1 to Day 28]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.
1. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tucson Cystic Fibrosis Center	Tucson	Arizona	United States	85750
2	Center for Cystic Fibrosis at Keck Medical Center of USC	Los Angeles	California	United States	90033
3	Stanford University Medical Center	Palo Alto	California	United States	94305
4	Augusta University	Augusta	Georgia	United States	30912
5	Tulane University	New Orleans	Louisiana	United States	70118
6	The Minnesota Cystic Fibrosis Center	Minneapolis	Minnesota	United States	55403
7	Washington University School of Medicine	Saint Louis	Missouri	United States	63130
8	Columbia University Cystic Fibrosis Program	New York	New York	United States	10027
9	Rainbow Babies and Children's Hospital / University Hospitals Cleveland Medical Center	Cleveland	Ohio	United States	44106
10	Nationwide Children's Hospital	Columbus	Ohio	United States	43205
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	Dell Children's Medical Center of Central Texas	Austin	Texas	United States	78723
13	The Royal Adelaide Hospital	Adelaide		Australia
14	Institute for Respiratory Health	Perth		Australia
15	Westmead Institute for Medical Research	Sydney		Australia