Cystic Fibrosis Lung, Pseudomonas Aeruginosa, Respiratory Infections, Recurrent, Chronic
Conditions
Keywords
Pseudomonas aeruginosa, cystic fibrosis, pulmonary infection, tobramycin, lung infection, EDTA, edetate calcium disodium
Brief summary
A double-blind, active-controlled, multiple-ascending dose, safety study of aerosolized RSP-1502 in subjects with cystic fibrosis Pseudomonas aeruginosa lung infection.
Detailed description
This dose escalation safety study will evaluate several doses of RSP-1502 or active control administered by inhalation for 14 days. Following determination of the MTD, a dose expansion cohort will receive RSP-1502 at the MTD versus active control administered by inhalation for 14 days. All subjects will be followed for 14 days after completion of dosing.
Interventions
DRUGRSP-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 (300 mg) and CaEDTA in a 5 mL solution.
Tobramycin inhalation solution is 300 mg tobramycin in 5 mL solution.
Sponsors
Respirion Pharmaceuticals Pty Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
12 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Males or females aged ≥18 years of age for cohorts 1-4; males or females ≥12 years of age for cohort 5. * 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 2 years preceding screening. * P. aeruginosa-positive sputum culture at screening. * Forced expiratory volume in 1 second (FEV1) ≥ 30 and ≤ 120% 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, and be capable and willing to complete all study visits and perform all study required procedures.
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 total 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 (subjects receiving inhaled tobramycin in conjunction with low dose azithromycin prior to study participation without evidence of ototoxicity may continue taking low dose azithromycin during the study). * 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: 1. The subject has not had a respiratory tract culture positive for these organisms within the 12 months before the date of informed consent. 2. 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 acute upper or lower respiratory tract infection or pulmonary exacerbation requiring changes in therapy (including systemic antibiotics), or other 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. * Vaping or smoking tobacco or any other substance within 1 month prior to screening and anticipated inability to refrain from vaping or smoking throughout the study. * Female subjects who are pregnant, lactating, or have a positive urine human chorionic gonadotropin (pregnancy) test, as determined by laboratory testing. * 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. * Has any other medical condition(s) which, in the opinion of the Principal Investigator, would jeopardize the safety of the study subject or impact the validity of the study results.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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, Day 2, and Day 14 | PR interval, QRS interval, QT interval |
Secondary
| Measure | Time frame |
|---|---|
| Pharmacokinetic parameters for CaEDTA | Day 1, Day 2, Day 14, and Day 28 |
| Pharmacokinetic parameters for tobramycin | Day 1, Day 2, Day 14, and Day 28 |
Countries
Australia, United States
Outcome results
None listed