Study of Cavosonstat (N91115) in CF Patients Who Are Heterozygous for F508del-CFTR and a Gating Mutation and Being Treated With Ivacaftor

Study Overview
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Brief Summary
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Cavosonstat (N91115) is being studied as a potential novel therapy for cystic fibrosis (CF), and this study assesses a target population of patients who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R).

Detailed Description
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Assess the effect of Cavosonstat (N91115) on lung function when added to preexisting treatment with ivacaftor in adult patients with CF who are heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R).

Official Title
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A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of N91115 for Efficacy and Safety in Patients With CF Heterozygous for F508del-CFTR + Gating Mutation Being Treated With 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: Confirmed diagnosis of CF, heterozygous for F508del-CFTR and a gating mutation that is approved for treatment with ivacaftor (G551D, G1244E, G1349D, G178R, G551S, S1251N, S1255P, S549N, or S549R) Have been treated with chronic ivacaftor twice daily for at least 6 months prior to Screening (date of consent) and are currently being treated with commercially available Ivacaftor Negative serum pregnancy test Weight ≥ 40 kg at screening Oxygen saturation by pulse oximetry ≥ 90% breathing ambient air, at screening Exclusion Criteria: Any acute infection, including acute upper or lower respiratory infections and pulmonary exacerbations that require treatment that has completed within 2 weeks of Study Day 1 or hospitalization discharge within 2 weeks of Study Day 1 Recent infection (per investigator discretion) with organisms associated with more rapid decline in pulmonary status, for example: 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 Blood hemoglobin < 10 g/dL at screening Serum albumin < 2.5 g/dL at screening Abnormal liver or renal function 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 (> 450 msec for men; > 470 msec for women) History of solid organ or hematological transplantation History of alcohol abuse or drug abuse (including cannabis, cocaine, and opioids) in the year prior to screening 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>Matching capsule (BID administration Q12H) | Drug: Placebo<br>* Matched Placebo capsule<br>* Other names: Control;|
| Experimental: Cavosonstat (N91115) 400 mg<br>Cavosonstat (N91115) at 400 mg dose (100 mg x 4 capsules) (BID administration Q12H) | Drug: Cavosonstat<br>* CFTR modulator that stabilizes CFTR<br>* Other names: N91115;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The absolute change in ppFEV1 in the N91115 treated group | Forced Expiratory Volume (FEV) absolute measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method. | Baseline, week 4 and 8 assessments | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The relative change from study baseline within the active treatment group in ppFEV1 values | Forced Expiratory Volume relative measurements comparing baseline to after 4 and 8 weeks of N91115 treatment. FEV1 is the volume of air that can forcibly be blown out in one second, after full inspiration. ppFEV1 (predicted for age, gender, and height) is calculated using the Hankinson method. | Baseline, week 4 and 8 assessments | 
| Absolute change from study baseline within the active treatment group in sweat chloride | Sweat chloride concentration measured by pilocarpine iontophoresis, a standard clinical laboratory technique. Sweat collection accomplished with the Wescor Macroduct System. | Baseline, week 4 and 8 assessments | 
| Changes in the respiratory domain of the Cystic Fibrosis Questionnaire - Revised, (CFQ-R) | Patient questionnaires will compare baseline scores on their respiratory symptoms to weeks 4 and 8 | Baseline, week 4 and 8 assessments | 
| Absolute change from baseline within the active treatment group in Patient Global Impression of Change | Patient questionnaires will compare baseline global impression of changes in health from baseline to weeks 4 and 8 | Baseline, week 4 and 8 assessments | 
| Safety as determined by adverse events assessment | Assessments of clinical laboratory values, electrocardiogram (ECG), pulmonary exacerbations, and vital signs | Baseline to 8 weeks treatment with a 28-day follow up period | 
| Pharmacokinetic Assessment of Maximum Plasma Concentration [Cmax] for N91115 & ivacaftor | Plasma collection for assessment of N91115 and ivacaftor Cmax | Weeks 1, 4 and 8 | 
| Pharmacokinetic Assessment of area under the plasma concentration verse time curve [AUC] for N91115 & ivacaftor | Plasma collection for assessment of N91115 and ivacaftor AUC | Weeks 1, 4 and 8 | 

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