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

Cystic Fibrosis Clinical Trial

— SNO4  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02275936
• Other study ID #: N91115-1CF-03
• Status: Completed
• Phase: Phase 1
• First received: October 14, 2014
• Last updated: November 3, 2016
• Start date: February 2015
• Est. completion date: July 2015

Study information

• Verified date: November 2016
• Source: Nivalis Therapeutics, Inc.
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 51
• Est. completion date: July 2015
• Est. primary completion date: July 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cystic Fibrosis
• Fibrosis

Intervention

Drug:
• N91115
S Nitrosoglutathione Reductase Inhibitor

Locations

Country	Name	City	State
United States	Children's CO	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama @ Birmingham	Birmingham	Alabama
United States	Boston Children's Hospital	Boston	Massachusetts
United States	University of North Carolina	Chapel Hill	North Carolina
United States	Northwestern University	Chicago	Illinois
United States	Cincinnati Children's Hospital	Cincinnati	Ohio
United States	Rainbow Babies and Children's Hospital - Case Medical Center	Cleveland	Ohio
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	National Jewish Health	Denver	Colorado
United States	Indiana University	Indianapolis	Indiana
United States	University of Iowa Children's Hospital	Iowa City	Iowa
United States	University of Minnesota	Minneapolis	Minnesota
United States	Columbia University	New York	New York
United States	The New York Presbyterian Hospital, Columbia University Medical Center	New York	New York
United States	Stanford University	Palo Alto	California
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Seattle Children's Hospital	Seattle	Washington
United States	Washington University	St. Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Nivalis Therapeutics, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Safety assessments based on clinical evaluations, laboratory assessments, and adverse events.		28 Days	Yes
Secondary	Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma	Area under the curve(AUC) assessments	28 Days	No
Secondary	Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma	Maximum plasma concentration (Cmax) determinations	28 Days	No
Secondary	Pharmacokinetic (PK) parameters of N91115 and its glucuronide metabolite in plasma	Ratio of parent:glucuronide metabolite	28 Days	No