Clinical trial NCT03647228: A Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-ENaCRx in Healthy Volunteers and Patients With Cystic Fibrosis
Official title: A Double-Blind, Placebo-Controlled, Dose-Escalation, Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of ION-827359, an Antisense Oligonucleotide Inhibitor of ENaC, Administered to Healthy Volunteers and Patients With Cystic Fibrosis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Subjects
Cystic Fibrosis
Keywords: ION-827359
ENaC
Lead sponsor: Ionis Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2018-08-27
Enrollment: 98
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Exclusion Criteria (Cystic Fibrosis Participants)

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. Abnormal liver function defined as \> 2 times upper limit of normal (ULN) for bilirubin, or 3 time ULN for ALT, AST, or alkaline phosphatase
   2. 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. Colonization with Burkholderia cepacia or M. abscessus

Primary outcomes:
measure: Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event
timeFrame: Up to 113 Days
Secondary outcomes:
measure: Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx
timeFrame: Up to 113 Days
measure: Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx
timeFrame: Up to 113 Days
measure: AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx
timeFrame: Up to 113 Days
measure: CL/F: apparent total clearance of IONIS-ENaCRx
timeFrame: Up to 113 Days
measure: t1/2λz: termination half-life of IONIS-ENaCRx
timeFrame: Up to 113 Days
measure: The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period
timeFrame: Up to 113 Days
Other outcomes:
Locations:
city: Essen
country: Germany
facility: Universitätsmedizin Essen
city: Frankfurt
country: Germany
facility: Universitätsklinikum Frankfurt
city: München
country: Germany
facility: Lungenheilkunde München-Pasing
city: Wythenshawe
country: United Kingdom
facility: Medicines Evaluation Unit
state: Manchester
city: Belfast
country: United Kingdom
facility: Celerion
state: Northern Ireland
city: Edinburgh
country: United Kingdom
facility: Western General Hospital
city: London
country: United Kingdom
facility: Adults Cystic Fibrosis King's College Hospital - Hambleden Wing (East)
city: London
country: United Kingdom
facility: Royal Brompton Hospital
Study officials:
References: