Study of LAU-7b in the Treatment of Cystic Fibrosis in Adults

Study Overview
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Brief Summary
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An International Phase II, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of LAU-7b administered once-daily for 6 months for the treatment of CF.

Detailed Description
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An International Phase II, double-blind, randomized, placebo-controlled study to evaluate the safety and efficacy of LAU-7b administered once-daily for 6 months for the treatment of CF. All patients will remain on their CF standard-of-care treatments over the trial duration. The goal for the treatment with LAU-7b in CF is to preserve lung function by reducing the persistent inflammation in the lung and to improve its capacity to defend against resistant bacteria such as Pseudomonas aeruginosa. The treatment regimen will consist of 6 consecutive dosing cycles of 21 days each, spaced by study drug-free periods of 7 days. A total of 136 eligible adult patients with CF will be randomized to receive 300 mg LAU-7b or placebo in a 1:1 ratio. The participation in the study will last about 7 months.

Official Title
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APPLAUD: A Double-Blind, Randomized, Placebo-Controlled, Phase II Study of the Efficacy and Safety of LAU-7b in the Treatment of Cystic Fibrosis in Adults

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: LAU-7b
* Drug: Placebo oral capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Screening FEV1 between 40% and 100% predicted value for age, gender and height, in patients capable of properly performing the test; History of pulmonary exacerbation, defined as at least one (1) pulmonary exacerbation in the year prior to Screening which resulted in documented intravenous or Oral antibiotics; Patients are eligible independently of their history of pulmonary Pseudomonas aeruginosa (PsA) infection and their PsA status at screening; If taking Kalydeco® (ivacaftor), Orkambi® (ivacaftor/lumacaftor), Symdeko® (ivacaftor/tezacaftor) or other commercially available CFTR modulator products, patients must be taking it for a minimum of 3 months prior to screening if naïve to CFTR modulators and 1 month if switched from another CFTR modulator product and deemed to tolerate it; No change in CF and allowed systemic chronic therapy for a minimum of 5 weeks prior to randomization, of which 2 weeks minimum are prior to screening; Female patients of child bearing potential should be on highly effective contraceptive methods during the study; Male patients with spouse or partner of child bearing potential, or pregnant, are eligible if they use an appropriate method of contraception. Exclusion Criteria: Pregnancy: due to the potential teratogenic effects of retinoids, pregnant women are NOT eligible; Breast milk feeding by study patient is NOT allowed; Clinically abnormal renal function: serum creatinine > 132 μM (1.5 mg/dL); Clinically abnormal liver function: Total bilirubin >1.5 x ULN (in the absence of demonstrated Gilbert's syndrome), alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2.5 x ULN; Patients with plasma retinol levels below 0.7 µM; Presence of nyctalopia or hemeralopia at enrolment, or any other serious retinal, ophthalmological condition; Presence of serious dermatological conditions at entry, including inflammatory or xerotic skin pathologies such as psoriasis or ichthyosis; Intake of chronic systemic steroids in the month prior to screening and during the study; History of acute infections (viral/bacterial/fungal) within 5 weeks prior to randomization, of which 2 weeks minimum are prior to screening, whether or not treated and resolved; Presence of infection with Burkholderia cepacia (including all species within the Burkholderia cepacia complex group, and Burkholderia gladioli) in the 12 months prior to screening; Patients with a confirmed diagnosis (as per the Cystic Fibrosis Foundation diagnostic criteria) of Allergic BronchoPulmonary Aspergillosis (ABPA) and actively being treated with corticosteroids and/or anti fungal agents.

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
Interventional Model Description: Double-blind, randomized, parallel groups and placebo-controlled trial.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LAU-7b<br>Active drug fenretinide (as LAU-7b capsules) | Drug: LAU-7b<br>* LAU-7b will be administered orally once-a-day with the first meal of the day as cycles of 21 days on, 7 days off, for a total of 6 planned cycles.<br>* Other names: fenretinide;|
| Placebo Comparator: Placebo<br>Placebo oral capsule (as inactive capsules identical to active arm) | Drug: Placebo oral capsule<br>* Placebo will be administered orally once-a-day with the first meal of the day as cycles of 21 days on, 7 days off, for a total of 6 planned cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Absolute change in percent predicted forced expiratory volume in 1 second (FEV1%) | Standardized, serial FEV1 measurements will be performed during the trial | From baseline to 24 weeks | 
| The safety and tolerability of LAU-7b will be assessed by the incidence of treatment emergent adverse events compared to placebo | This will be assessed through serial assessments and ad-hoc assessments | From Baseline to 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of patients achieving normalization of the arachidonic acid, docosahexaenoic acid and their ratio in phospholipids | This will be assessed through serial blood sampling during the trial | From baseline to 28 weeks | 
| The absolute and relative (%) change in FEV1 percent predicted at 3, 7, 11, 15 and 28 weeks into the trial | Standardized, serial FEV1 measurements will be performed during the trial | From baseline to 3, 7, 11, 15 and 28 weeks into the trial | 
| The time to first protocol-defined pulmonary exacerbation | Reports of pulmonary exacerbation during the trial | From baseline to 28 weeks | 
| The incidence of protocol-defined pulmonary exacerbation | Reports of pulmonary exacerbation during the trial | From baseline to 28 weeks | 
| The time to first change and usage of antibiotic (other than chronic inhaled antibiotics already started prior to trial or oral chronic azithromycin) | Reports of pulmonary exacerbation and their treatment during the trial | From baseline to 28 weeks | 
| The change from baseline of systemic markers of inflammation in blood | This will be assessed through serial blood sampling during the trial | From baseline to 28 weeks | 
| The change from screening of the body weight and calculated Body Mass Index (BMI) | This will be assessed through serial weighing during the trial | From screening to 28 weeks | 
| The overall change from screening of the Pseudomonas aeruginosa density (colony forming units) in the sputum | This will be assessed through induced sputum on 3 occasions during the trial | From screening to Weeks 11 and 24 | 
| The impact (from baseline) on overall health, daily life, perceived well-being and symptoms measured with the Cystic Fibrosis Questionnaire-Revised (CFQ-R) | This will be assessed through administration of the questionnaire at planned times during the trial | From baseline to 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Inflammation, Essential Fatty Acids, Inflammation resolution, Docosahexaenoic acid, Lung function