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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

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ClinicalTrials.gov Identifier: NCT03647228
Recruitment Status : Recruiting
First Posted : August 27, 2018
Last Update Posted : March 8, 2019
Sponsor:
Information provided by (Responsible Party):
Ionis Pharmaceuticals, Inc.

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 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 participants with cystic fibrosis. The study will enroll approximately 88 subjects.

The study will consist of 4 single-dose randomized cohorts. Subjects enrolled will receive a single inhaled dose of the Study Drug (IONIS-ENaCRx or placebo) on Day 1.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 88 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 : December 13, 2018
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Cystic Fibrosis

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.




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

Secondary Outcome Measures :
  1. Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  2. Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  3. AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  4. CL/F: apparent total clearance of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  5. t1/2λz: termination half-life of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  6. The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period [ Time Frame: Up to 113 Days ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03647228


Contacts
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Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com

Locations
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United Kingdom
Celerion Recruiting
Belfast, Northern Ireland, United Kingdom, BT9 6AD
Contact    +44 28 90 554001    fiona.mcneilly@celerion.com   
Sponsors and Collaborators
Ionis Pharmaceuticals, Inc.

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Responsible Party: Ionis Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT03647228     History of Changes
Other Study ID Numbers: ION-827359-CS1
2018-002621-27 ( EudraCT Number )
First Posted: August 27, 2018    Key Record Dates
Last Update Posted: March 8, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
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Cystic Fibrosis
Pancreatic Diseases
Digestive System Diseases
Lung Diseases
Respiratory Tract Diseases
Genetic Diseases, Inborn
Infant, Newborn, Diseases