Cystic Fibrosis, Healthy Subjects
Conditions
Keywords
ION-827359, ENaC
Brief summary
This Phase 1/2a study is a double-blinded (subject and Investigator), randomized, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of single and multiple nebulized doses of IONIS-ENaCRx.
Detailed description
This study will be conducted in 3 parts: a single ascending dose (SAD) leading to a multiple ascending dose (MAD) in healthy volunteers, followed by a MAD in patients with cystic fibrosis. The study will enroll up to 88 participants. The study will consist of 4 single-dose randomized cohorts. Participants enrolled will receive a single inhaled dose of the Study Drug (IONIS-ENaCRx or placebo) on Day 1.
Interventions
DRUGIONIS-ENaCRx
Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.
DRUGPlacebo
Placebo comparator calculated volume to match active comparator inhaled or nebulized.
Sponsors
Ionis Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
(Healthy Volunteers) 1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. 2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method 3. Willing to refrain from strenuous exercise/activity for at least 72 hours prior to study visits 4. Body mass index (BMI) \< 35 kg/m2 with a minimum weight of 45 kg 5. Normal diffusing capacity in the lung (≥ 80% predicted) at Screening
Exclusion criteria
(Healthy Volunteers) 1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to: 1. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg 2. Positive test (including trace) for blood on urinalysis 3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN), fasting blood glucose, potassium \> upper limit of normal (ULN) 4. Platelet count \< LLN 2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 3. Respiratory infection within 4 weeks of Study Day 1 4. Presence or past history of CS chronic respiratory disease, including any current history (or within 2 years) of asthma. History of allergic rhinitis is acceptable 5. Forced expiratory volume in 1 second (FEV1) \< 80% of predicted at Screening or an FEV1/FVC ratio of \< 0.7 6. Smoking of a tobacco or nicotine-containing product within the previous 6 months (use of a nicotine patch is permitted) or a smoking history of ≥ 10 pack years 7. Any CS finding on chest radiograph 8. Uncontrolled hypertension (blood pressure \[BP\] \> 160/100 mm Hg) at Screening 9. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer 10. Any history of previous treatment with an oligonucleotide 11. Regular use of alcohol within 6 months prior to screening or hard drugs within 1 year prior to screening, or positive urine drug screen at Screening 12. Blood donation of 50 to 499 mL within 30 days of screening or of \> 499 mL within 60 days of screening Inclusion Criteria (Cystic Fibrosis Participants) 1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. 2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method 3. Confirmed diagnosis of CF by seat chloride and/or genetics by referring clinician 4. FEV1 \>/= 50% of predicted 5. Stable CF disease as judged by the Investigator 6. Weight \> 40 kg
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event | Up to 113 Days |
Secondary
| Measure | Time frame |
|---|---|
| Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx | Up to 113 Days |
| Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx | Up to 113 Days |
| CL/F: apparent total clearance of IONIS-ENaCRx | Up to 113 Days |
| t1/2λz: termination half-life of IONIS-ENaCRx | Up to 113 Days |
| The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period | Up to 113 Days |
| AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx | Up to 113 Days |
Countries
Germany, United Kingdom
Outcome results
None listed