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

• Sponsor: Ionis Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03647228
• Collaborator: (none)
• Enrollment: 98
• Locations: 8
• Arms: 2
• Actual Duration (Months): 22
• Patients Per Site: 12.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy Subjects; Cystic Fibrosis	Drug: IONIS-ENaCRx; Drug: Placebo	Phase 1

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 98 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: Dec 13, 2018
• Actual Primary Completion Date: Oct 13, 2020
• Actual Study Completion Date: Oct 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: IONIS-ENaCRx Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.	Drug: IONIS-ENaCRx; Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.
Placebo Comparator: Placebo Placebo comparator calculated volume to match active comparator inhaled or nebulized.	Drug: Placebo; Placebo comparator calculated volume to match active comparator inhaled or nebulized.

Outcome Measures

Primary Outcome Measures

1. Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event [Up to 113 Days]

Secondary Outcome Measures

1. Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx [Up to 113 Days]

2. Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx [Up to 113 Days]

3. AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx [Up to 113 Days]

4. CL/F: apparent total clearance of IONIS-ENaCRx [Up to 113 Days]

5. t1/2λz: termination half-life of IONIS-ENaCRx [Up to 113 Days]

6. The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period [Up to 113 Days]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts 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:

2. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg

3. Positive test (including trace) for blood on urinalysis

4. 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)

5. Platelet count < LLN

6. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

7. Respiratory infection within 4 weeks of Study Day 1

8. 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

9. Forced expiratory volume in 1 second (FEV1) < 80% of predicted at Screening or an FEV1/FVC ratio of < 0.7

10. 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

11. Any CS finding on chest radiograph

12. Uncontrolled hypertension (blood pressure [BP] > 160/100 mm Hg) at Screening

13. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer

14. Any history of previous treatment with an oligonucleotide

15. 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

16. 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:

2. Abnormal liver function defined as > 2 times upper limit of normal (ULN) for bilirubin, or 3 time ULN for ALT, AST, or alkaline phosphatase

3. Platelet count < LLN

4. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1

5. Respiratory infection within 4 weeks of Study Day 1

6. Colonization with Burkholderia cepacia or M. abscessus

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Universitätsmedizin Essen	Essen		Germany	45239
2	Universitätsklinikum Frankfurt	Frankfurt		Germany	D-60589
3	Lungenheilkunde München-Pasing	München		Germany	81241
4	Medicines Evaluation Unit	Wythenshawe	Manchester	United Kingdom	M23 9QZ
5	Celerion	Belfast	Northern Ireland	United Kingdom	BT9 6AD
6	Western General Hospital	Edinburgh		United Kingdom	EH4 2XU
7	Adults Cystic Fibrosis King's College Hospital - Hambleden Wing (East)	London		United Kingdom	SE5 9RS
8	Royal Brompton Hospital	London		United Kingdom	SW3 6HP

Sponsors and Collaborators

• Ionis Pharmaceuticals, Inc.

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Ionis Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT03647228
• Other Study ID Numbers: ION-827359-CS1; 2018-002621-27
• First Posted: Aug 27, 2018
• Last Update Posted: Feb 4, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by Ionis Pharmaceuticals, Inc.: ION-827359; ENaC
• Additional relevant MeSH terms: Cystic Fibrosis; Fibrosis

Study Results

No Results Posted as of Feb 4, 2021