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

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

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.

Study Overview

• Status: Completed
• Conditions: Cystic Fibrosis
• Intervention / Treatment: Drug: LAU-7b; Drug: Placebo oral capsule

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 166
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • New Lambton Heights, New South Wales, Australia, 2305
      • Respiratory Medicine, John Hunter Hospital
    • Sydney, New South Wales, Australia, 2050
      • Department of Respiratory Medicine, Royal Prince Alfred Hospital
    • Westmead, New South Wales, Australia, 2145
      • Department of Respiratory and Sleep Medicine, Westmead Hospital
  • Queensland
    • Brisbane, Queensland, Australia, 4101
      • Mater Misericordiae Ltd
  • Victoria
    • Clayton, Victoria, Australia, 3168
      • Monash Lung and Sleep, Monash Health
    • Melbourne, Victoria, Australia, 3004
      • The Alfred Hospital
  • Western Australia
    • Nedlands, Western Australia, Australia, 6009
      • Institute of Respiratory Health, Harry Perkins Institute
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
      • Pacific Lung Research Institute at St. Paul's Hospital
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • The Ottawa Hospital Center for Practice-Changing Research
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
      • Centre d'études cliniques CIUSS SLJ, Hôpital Chicoutimi
    • Montréal, Quebec, Canada, H4A 3J1
      • McGill University Health Center
    • Montréal, Quebec, Canada, H2X2P1
      • Centre Hospitalier de l'Universite de Montreal
    • Québec City, Quebec, Canada, G1V 4G5
      • Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Quebec
• United States
  • California
    • Long Beach, California, United States, 90806
      • Long Beach Memorial Medical Center
    • Los Angeles, California, United States, 90227
      • Children's Hospital Los Angeles
    • Sacramento, California, United States, 95817
      • UC Davis Medical Center, Division of Pulmonary & Critical Care Medicine
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Florida
    • Gainesville, Florida, United States, 32610
      • Division of pulmonary, critical care and sleep medicine, University of Florida
    • Hollywood, Florida, United States, 33021
      • Memorial Healthcare System, Joe DiMaggio Children's Hospital Cystic Fibrosis & Pulmonary Center
    • Pensacola, Florida, United States, 32603
      • Avanza Medical Research Center
  • Idaho
    • Boise, Idaho, United States, 83712
      • St-Luke's CF Center of Idaho
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • Kansas
    • Kansas City, Kansas, United States, 66103
      • University of Kansas Medical Center
  • Maine
    • Portland, Maine, United States, 04102
      • Maine Medical Center Cystic Fibrosis Research
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Health System
    • Detroit, Michigan, United States, 48201
      • Wayne State University, Harper University Hospital
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • The Minnesota Cystic Fibrosis Center, University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University Medical School
  • New Jersey
    • Morristown, New Jersey, United States, 07962
      • Morristown Medical Center, NJ Adult Cystic Fibrosis Center
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers University Clinical Research Center, RW Johnson University Hospital
  • New York
    • Albany, New York, United States, 12208
      • Albany Medical College
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center, Rainbow Babies and Children's Hospital
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Oregon
    • Portland, Oregon, United States, 97239
      • Cystic Fibrosis Center, Doernbecher Children's Hospital, Oregon Health & Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15224
      • Children's Hospital of Pittsburgh of UPMC
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • University of Utah
  • Virginia
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin, Div of Pulmonary and Critical Care Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo oral capsule (as inactive capsules identical to active arm)	Drug: Placebo oral capsule; 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.
Experimental: LAU-7b; Active drug fenretinide (as LAU-7b capsules)	Drug: LAU-7b; 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.; Other Names: fenretinide

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
The change in metabolipidomic profile and in markers of oxidative stress in blood	This will be assessed through serial blood sampling during the trial	From baseline to 28 weeks
The change in metabolipidomic profile in blood, the systemic markers of inflammation in blood, the FEV1, the body weight and calculated BMI	Only in patients who experience a pulmonary exacerbation requiring intravenous antibiotics, this will be assessed prior to- and after the intravenous antibiotic course.	From baseline to 28 weeks
The change from baseline of systemic bone formation and resorption biomarkers	This will be assessed through blood sampling on 2 occasions during the trial	Baseline and 24 weeks

Collaborators and Investigators

• Sponsor: Laurent Pharmaceuticals Inc.
• Collaborators: Cystic Fibrosis Foundation
• Investigators: Study Chair: Larry C Lands, MD PhD, McGill Uinversity Health Centre; Study Chair: Michael W Konstan, MD, Rainbow Babies and Children's Hospital/ University Hospitals Cleveland Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): October 10, 2018
• Primary Completion (Actual): September 15, 2021
• Study Completion (Actual): September 15, 2021

Study Registration Dates

• First Submitted: February 21, 2017
• First Submitted That Met QC Criteria: August 25, 2017
• First Posted (Actual): August 29, 2017

Study Record Updates

• Last Update Posted (Actual): October 5, 2021
• Last Update Submitted That Met QC Criteria: October 3, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: Inflammation; Lung function; Docosahexaenoic acid; Inflammation resolution; Essential Fatty Acids
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Respiratory Tract Diseases; Lung Diseases; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Pancreatic Diseases; Fibrosis; Cystic Fibrosis; Physiological Effects of Drugs; Antineoplastic Agents; Protective Agents; Anticarcinogenic Agents; Fenretinide
• Other Study ID Numbers: LAU-14-01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No