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SNO4: Study of N91115 in Patients With Cystic Fibrosis Homozygous F508del-CFTR Mutation

Sponsor
Nivalis Therapeutics, Inc. (Industry)
Overall Status
Completed
CT.gov ID
NCT02275936
Collaborator
(none)
51
Enrollment
19
Locations
4
Arms
4.9
Duration (Months)
2.7
Patients Per Site
0.5
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This Phase 1b study in F508del-CFTR homozygous CF patients is being conducted to assess the safety of N91115 as the sole cystic fibrosis transmembrane conductance regulator (CFTR) modulator at doses near the expected therapeutic exposure level in preparation for Phase 2 studies of N91115 added to the CFTR modulator combination lumacaftor/ivacaftor when launched.

Condition or Disease Intervention/Treatment Phase
Phase 1

Detailed Description

Study procedures, frequency and timing are provided in the attached study schema. Adverse events and concomitant medication will be monitored throughout the study from informed consent signing until end of study participation. A Data Monitoring Committee (DMC) will also review unblinded safety data on a monthly basis throughout the study. Limitations on bronchodilators for pulmonary assessments prior to study drug dosing are described below except in emergent situations.

  • Short acting β-agonists and anticholinergics will be held for at least 4 hours

  • Long acting β-agonists dosed twice daily will be held for at least 12 hours

  • Long acting β-agonists dosed once daily and long acting anticholinergics will be held for at least 24 hours

Screening (Day -28 to Day -3):

Patients will sign the informed consent and undergo procedures to determine eligibility including pregnancy testing, demographic information, medical history, and genotype by historical confirmation or blood sample confirmation (as applicable), height and weight, 12-Lead electrocardiogram (ECG), 48-hour Holter monitoring, chemistry, hematology, full physical examination, sweat chloride, smoking and alcohol history, spirometry, sputum microbiology, urinalysis and vital signs.

Day 1 Predose (Day -2 to -1) Patients will return to the clinic to reconfirm eligibility and assess any changes in medical history and pregnancy status. An abbreviated physical examination focusing on cardiovascular, pulmonary and gastrointestinal systems plus an assessment of weight will be conducted. The following will be obtained: 12-lead ECG, abbreviated physical exam, blood for DNA (optional), blood for leukocyte messenger ribonucleic acid (mRNA), blood inflammatory biomarkers, cystic fibrosis questionnaire-revised (CFQ-R), O2 Sat, patient global impression of change (PGIC), safety labs, serum pharmacokinetics (PK), spirometry, sputum microbiology, sweat chloride (SC) (if more than 2 weeks since the screening value was obtained), and vital signs. Sites may choose to perform any of these assessments on Day -2, Day -1 or Day 1 predose except for serum PK that starts Day 1 predose and vital signs that are done Day 1 predose.

Dosing and Food Intake:

Patients will take their dose of study drug every 12 hours at approximately the same time each morning and night. There are no restrictions related to food intake.

Dosing Days 1 and 2:

On Day 1, patients will be observed for at least 4 hours following the first dose of study drug. Patients return to the clinical site on Day 2 for a predose PK sample that is 24 hours after their first dose. Patients will be observed for at least 2 hours after the second dose on Day 2.

Days 3-28:

Patients self-administer study drug at approximately the same time each morning and evening with the exception that the morning doses on clinic Days 7, 14, 21 and 28, which will be administered and witnessed in the clinic.

Day 7 (Dosing in Clinic):

On Day 7, patients will return to the clinic to monitor any changes in health status and for an abbreviated physical exam, 12-Lead ECG, O2 Sat, safety labs, PK, spirometry, study drug compliance, SC and vital signs.

Day 14 (Dosing in Clinic):

On Day 14, patients will return to the clinic to monitor any changes in health status and for an abbreviated physical exam, urine pregnancy, 12-lead ECG, blood inflammatory biomarkers, CFQ-R, O2 Sat, safety labs, PK, spirometry, study drug compliance, SC and vital signs.

Day 21 (Dosing in Clinic):

On Day 21, patients will return to the clinic to monitor any changes in health status and for an abbreviated physical exam, 12-Lead ECG, O2 Sat, safety labs, PK, spirometry, study drug compliance, SC and vital signs.

Day 28 (Dosing in Clinic):

On Day 28 patients will return to the clinic to monitor any changes in health status and for an abbreviated physical exam, 12-Lead ECG, blood for DNA (optional), blood for leukocyte mRNA, blood inflammatory biomarkers, CFQ-R, urine pregnancy, O2 Sat, PGIC, safety labs, PK, spirometry, sputum microbiology, study drug compliance, SC, weight, and vital signs.

Day 42 (Final study day 2 weeks after last dose):

On Day 42 (± 2 days) study follow-up assessments include: abbreviated physical exam, blood inflammatory biomarkers, O2 Sat, PGIC, spirometry, SC, weight, and vital signs.

Study Design

Study Type:
Interventional
Actual Enrollment :
51 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
A Phase 1b, Randomized, Double-Blind, Placebo-Controlled, Parallel, Group Study of N91115 to Evaluate Safety and Pharmacokinetics in Patients With Cystic Fibrosis Homozygous for the F508del-CFTR Mutation
Study Start Date :
Feb 1, 2015
Actual Primary Completion Date :
Jul 1, 2015
Actual Study Completion Date :
Jul 1, 2015

Arms and Interventions

Arm Intervention/Treatment
Experimental: Group 1 - 50 mg

Every 12 hour oral dosing of N91115 for 28 days

Drug: N91115
S Nitrosoglutathione Reductase Inhibitor
Other Names:
  • Cavosonstat

    		•
    Experimental: Group 2 - 100 mg

    Every 12 hour oral dosing of N91115 for 28 days

    Drug: N91115
    S Nitrosoglutathione Reductase Inhibitor
    Other Names:
  • Cavosonstat

    		•
    Experimental: Group 3 - 200 mg

    Every 12 hour oral dosing of N91115 for 28 days

    Drug: N91115
    S Nitrosoglutathione Reductase Inhibitor
    Other Names:
  • Cavosonstat

    		•
    Placebo Comparator: Group 4 - Placebo

    Every 12 hour oral dosing of placebo comparator for 28 days

    Drug: N91115
    S Nitrosoglutathione Reductase Inhibitor
    Other Names:
  • Cavosonstat

    		•

    Outcome Measures

    Primary Outcome Measures

    1. Safety assessments based on clinical evaluations, laboratory assessments, and adverse events. [28 Days]

    Secondary Outcome Measures

    1. Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma [28 Days]

      Area under the curve(AUC) assessments

    2. Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma [28 Days]

      Maximum plasma concentration (Cmax) determinations

    3. Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma [28 Days]

      Ratio of parent:glucuronide metabolite

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 80 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:

    1. Male or female, age ≥ 18 years with confirmed diagnosis of CF, homozygous for the F508del-CFTR mutation based on historical results generated by Ambry Genetics within the past two years or if unavailable, confirmed by testing done within the past 28 days

    2. Sweat chloride ≥ 60 (milliequivalents) mEq/L, by quantitative pilocarpine iontophoresis test (QPIT) at screening

    3. Weight ≥ 40 kg at screening

    4. Forced expiratory volume (FEV1) ≥ 40% of predicted normal for age, gender, and height (Hankinson standards) pre- or post-bronchodilator value, at screening

    5. Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening

    6. Hematology, clinical chemistry and urinalysis results with no clinically significant abnormalities that would interfere with the study assessments at screening

    Exclusion Criteria:

    1. Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment or hospitalization within 2 weeks of Study Day 1

    2. Any change in chronic therapies for CF lung disease (e.g., Ibuprofen, Pulmozyme®, hypertonic saline, Azithromycin, Tobi®, Cayston®) within 4 weeks of Study Day 1

    3. Blood hemoglobin < 10 g/dL at screening

    4. Serum albumin < 2.5 g/dL at screening

    5. Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) in 3 or more of the following: aspartate aminotransferase (AST), alanine aminotransferase (ALT), g-glutamyl transferase (GGT), alkaline phosphatase (ALP), or total bilirubin at screening

    6. History of abnormal renal function (creatinine clearance < 50 mL/min using Cockcroft-Gault equation) within a year of screening

    7. History, including the screening assessment, of ventricular tachycardia or other ventricular arrhythmias

    8. History, including the screening assessment, of prolonged cardiac QT interval and/or QTcF (QT with Fridericia's correction) interval (> 450 msec)

    9. History of solid organ or hematological transplantation

    10. History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening

    11. Use of continuous (24 hr/day) or nocturnal supplemental oxygen

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 University of Alabama @ Birmingham Birmingham Alabama United States 35294
    2 Stanford University Palo Alto California United States 94304
    3 Children's CO Aurora Colorado United States 80045
    4 National Jewish Health Denver Colorado United States 80206
    5 Northwestern University Chicago Illinois United States 60611
    6 Indiana University Indianapolis Indiana United States 46202
    7 University of Iowa Children's Hospital Iowa City Iowa United States 52242
    8 Johns Hopkins Hospital Baltimore Maryland United States 21287
    9 Boston Children's Hospital Boston Massachusetts United States 02115
    10 University of Minnesota Minneapolis Minnesota United States 55455
    11 Washington University St. Louis Missouri United States 63110
    12 Columbia University New York New York United States 10032
    13 The New York Presbyterian Hospital, Columbia University Medical Center New York New York United States 10032
    14 University of North Carolina Chapel Hill North Carolina United States 27599
    15 Cincinnati Children's Hospital Cincinnati Ohio United States 45229
    16 Rainbow Babies and Children's Hospital - Case Medical Center Cleveland Ohio United States 44106
    17 Nationwide Children's Hospital Columbus Ohio United States 43205
    18 Children's Hospital of Philadelphia Philadelphia Pennsylvania United States 19104
    19 Seattle Children's Hospital Seattle Washington United States 98105

    Sponsors and Collaborators

    • Nivalis Therapeutics, Inc.

    Investigators

    • Principal Investigator: Scott Donaldson, MD, University of North Carolina

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    Nivalis Therapeutics, Inc.
    ClinicalTrials.gov Identifier:
    NCT02275936
    Other Study ID Numbers:
    • N91115-1CF-03
    First Posted:
    Oct 27, 2014
    Last Update Posted:
    Nov 6, 2016
    Last Verified:
    Nov 1, 2016
    Keywords provided by Nivalis Therapeutics, Inc.
    N91115
    Cavosonstat
    Additional relevant MeSH terms:
    Cystic Fibrosis
    Fibrosis

    Study Results

    No Results Posted as of Nov 6, 2016