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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.

Tracking Information
First Submitted Date  ICMJE August 23, 2018
First Posted Date  ICMJE August 27, 2018
Last Update Posted Date March 8, 2019
Actual Study Start Date  ICMJE December 13, 2018
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 23, 2018)
Safety and Tolerability as Measured by the Number of Participants with at least one Treatment-Emergent Adverse Event [ Time Frame: Up to 113 Days ]
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT03647228 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: August 23, 2018)
  • Cmax: maximum observed drug concentration in plasma of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  • Tmax: time taken to reach maximal concentration in plasma of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  • AUCt: area under the plasma concentration-time curve from time zero to time t for IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  • CL/F: apparent total clearance of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  • t1/2λz: termination half-life of IONIS-ENaCRx [ Time Frame: Up to 113 Days ]
  • The amount of administered dose of IONIS-ENaCRx excreted in urine over a 24-hour period [ Time Frame: Up to 113 Days ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Condition  ICMJE Healthy Subjects
Intervention  ICMJE
  • Drug: IONIS-ENaCRx
    Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.
  • Drug: Placebo
    Placebo comparator calculated volume to match active comparator inhaled or nebulized.
Study Arms  ICMJE
  • Experimental: IONIS-ENaCRx
    Ascending single and multiple doses of IONIS-ENaCRx inhaled or nebulized.
    Intervention: Drug: IONIS-ENaCRx
  • Placebo Comparator: Placebo
    Placebo comparator calculated volume to match active comparator inhaled or nebulized.
    Intervention: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 6, 2019)
88
Original Estimated Enrollment  ICMJE
 (submitted: August 23, 2018)
56
Estimated Study Completion Date  ICMJE October 2019
Estimated Primary Completion Date October 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Ionis Pharmaceuticals 800-679-4747 patients@ionisph.com
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03647228
Other Study ID Numbers  ICMJE ION-827359-CS1
2018-002621-27 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Ionis Pharmaceuticals, Inc.
Study Sponsor  ICMJE Ionis Pharmaceuticals, Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Ionis Pharmaceuticals, Inc.
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP