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

Cystic Fibrosis Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03647228
• Other study ID #: ION-827359-CS1
• Secondary ID: 2018-002621-27
• Status: Completed
• Phase: Phase 1
• Start date: December 13, 2018
• Est. completion date: October 13, 2020

Study information

• Verified date: February 2021
• Source: Ionis Pharmaceuticals, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: October 13, 2020
• Est. primary completion date: October 13, 2020
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis
• Healthy Subjects

Intervention

Drug:
• IONIS-ENaCRx
Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.
• Placebo
Placebo comparator calculated volume to match active comparator inhaled or nebulized.

Locations

Country	Name	City	State
Germany	Universitätsmedizin Essen	Essen
Germany	Universitätsklinikum Frankfurt	Frankfurt
Germany	Lungenheilkunde München-Pasing	München
United Kingdom	Celerion	Belfast	Northern Ireland
United Kingdom	Western General Hospital	Edinburgh
United Kingdom	Adults Cystic Fibrosis King's College Hospital - Hambleden Wing (East)	London
United Kingdom	Royal Brompton Hospital	London
United Kingdom	Medicines Evaluation Unit	Wythenshawe	Manchester

Sponsors (1)

Lead Sponsor	Collaborator
Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

Germany,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event		Up to 113 Days
Secondary	Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx		Up to 113 Days
Secondary	Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx		Up to 113 Days
Secondary	AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx		Up to 113 Days
Secondary	CL/F: apparent total clearance of IONIS-ENaCRx		Up to 113 Days
Secondary	t1/2?z: termination half-life of IONIS-ENaCRx		Up to 113 Days
Secondary	The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period		Up to 113 Days