Study of Cavosonstat (N91115) in Patients With CF Homozygous for the F508del-CFTR Mutation

Study Overview
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Brief Summary
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This will be a double-blind, randomized, placebo-controlled, parallel group study. The purpose of this study is to investigate the efficacy and safety of Cavosonstat (N91115) in adult patients with CF who are homozygous for the F508del-CFTR mutation and being treated with lumacaftor/ivacaftor (Orkambi™).

Detailed Description
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Primary Objective: Assess the efficacy of N91115 at 12 weeks when added to preexisting treatment with lumacaftor/ivacaftor in adult patients with CF who are homozygous for the F508del-CFTR mutation Secondary Objectives: Assess the effect of N91115 added to lumacaftor/ivacaftor on safety Assess the effect of lumacaftor/ivacaftor added to N91115 on the pharmacokinetics of N91115, lumacaftor, and ivacaftor

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of N91115 to Evaluate Efficacy and Safety in Patients With Cystic Fibrosis Who Are Homozygous for the F508del-CFTR Mutation Treated With Lumacaftor/Ivacaftor

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: Cavosonstat
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have been treated with lumacaftor/ivacaftor for at least 8 weeks prior to Day 1 (start of dosing) A history of Sweat Chloride (SC) ≥ 60 mEq/L by quantitative pilocarpine iontophoresis test (QPIT) (either before or after starting lumacaftor/ivacaftor treatment) Body weight ≥ 40 kg ppFEV1 40 - 85 % predicted (inclusive) at screening Oxygen saturation ≥ 90% breathing ambient air at screening Exclusion Criteria: Any acute infection that requires treatment or hospitalization within 2 weeks of Study Day 1 Colonization with organisms associated with more rapid decline in pulmonary status, such as Burkholderia cenocepacia, Burkholderia dolosa, and Mycobacterium abscessus Any change in the regimen for chronic therapies for CF lung disease (e.g., Pulmozyme®, hypertonic saline, Azithromycin, TOBI®, Cayston®) within 4 weeks of Study Day 1 Are pregnant, planning a pregnancy, or breast-feeding at screening Blood hemoglobin < 10 g/dL at screening Serum albumin < 2.5 g/dL at screening Abnormal liver function defined as ≥ 3 x upper limit of normal (ULN) History of abnormal renal function within 3 months of screening History of ventricular tachycardia or other clinically significant ventricular arrhythmias History, including the screening assessment, of prolonged QT and/or QTcF (Fridericia's correction) interval History of solid organ or hematological transplantation History of alcohol abuse or drug abuse Ongoing participation in another therapeutic clinical trial Use of continuous (24 hr/day) or nocturnal supplemental oxygen

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo Capsule | Drug: Placebo<br>* Control sample with only capsule excipients and fillers<br>* Other names: control;|
| Experimental: Cavosonstat (N91115) 200 mg<br>Cavosonstat (N91115) 200 mg twice daily (BID) | Drug: Cavosonstat<br>* GSNOR inhibitor<br>* Other names: N91115;|
| Experimental: Cavosonstat (N91115) 400 mg<br>Cavosonstat (N91115) 400 mg BID | Drug: Cavosonstat<br>* GSNOR inhibitor<br>* Other names: N91115;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change from baseline in percent predicted FEV1 (ppFEV1) | Forced Expiratory Volume in one second (FEV1) from before study (Baseline) to after 12 weeks of N91115 treatment | From baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative change from baseline in ppFEV1 | Forced Expiratory Volume in one second (FEV1) from before study (Baseline) to after 12 weeks of N91115 treatment | baseline to 12 weeks | 
| Absolute change from baseline in sweat chloride | A sweat chloride measurement on the skin at study start and after 12 weeks of N91115 | baseline to 12 weeks | 
| Absolute change from baseline in Cystic Fibrosis Questionnaire -Revised CFQ-R (respiratory symptom scale) | Comparison of the Questionnaire from study start to 16 weeks | baseline to 16 weeks | 
| Absolute change from baseline in body mass index (BMI) | Assessment of change in body mass index from study start to after 12 weeks of N91115 | baseline to 12 weeks | 
| Absolute change from baseline in Patient Global Impression of Change (PGIC) | Patient reported outcome journal | baseline to 12 weeks | 
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]) | Any adverse events assessment including clinical laboratory values, electrocardiogram (ECG), pulmonary exacerbations, or vital sign changes | baseline to 16 weeks | 
| Pharmacokinetic Measurements of Maximum Plasma Concentration [Cmax], of N91115, lumacaftor, and ivacaftor | Maximum Plasma Concentration [Cmax] measurements of N91115, lumacaftor and ivacaftor | baseline to 12 weeks | 
| Pharmacokinetic Measurements of Area Under the Curve (AUC) for N91115, Ivacaftor and lumacaftor | AUC measurements of N91115, lumacaftor and ivacaftor | baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cystic Fibrosis, N91115, Cavosonstat