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

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.; Other Names: Placebo
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 were performed during the trial by the clinical sites using standardized spirometers. All spirometry measurements were centrally read and validated by the spirometry provider, Vitalograph. The outcome measure is presented using the Least Squares Mean at the Week 24 time point and the Least Squares Mean of all post-baseline time points through Week 24 averaged.	From baseline to 24 weeks
Summary of Treatment Emergent Adverse Events With ≥ 10% Incidence	This was assessed through adverse event monitoring at all visits, including spontaneously reported events and those obtained through serial probing of the subjects, and from safety laboratory tests	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	Assessed through 4 blood sampling occasions during the trial. Plasma samples were analyzed using a validated LC/MS method and corrected for phospholipid content. Highest proportion of normalization during treatment was determined versus analyte ranges obtained from a group of 20 healthy, non-CF individuals.	From baseline to 28 weeks
The Absolute Change in FEV1 Percent Predicted at 3, 7, 11, 15, 24 and 28 Weeks Into the Trial	Standardized, serial FEV1 measurements were performed during the trial by the clinical sites using standardized spirometers. All spirometry measurements were centrally read and validated by the spirometry provider, Vitalograph.	From baseline to 3, 7, 11, 15, 24 and 28 weeks into the trial
The Relative (%) Change in FEV1 Percent Predicted at 3, 7, 11, 15, 24 and 28 Weeks Into the Trial	Standardized, serial FEV1 measurements were performed during the trial by the clinical sites using standardized spirometers. All spirometry measurements were centrally read and validated by the spirometry provider, Vitalograph.	From baseline to 3, 7, 11, 15, 24 and 28 weeks into the trial
The Time to First Protocol-Defined Pulmonary Exacerbation	Reports of IV antibiotics-treated pulmonary exacerbations during the trial that meet the Fuch's criteria and after the first treatment cycle.	From baseline to 28 weeks
The Number Per Subject of Protocol-Defined Pulmonary Exacerbations (PEx) During the Trial	The number per subject of Protocol-Defined IV antibiotics-treated pulmonary exacerbations (events) during the trial that meet the Fuch's criteria. Also presented are the number per subject of IV antibiotics-treated pulmonary exacerbations and combined number per subject of IV- or Oral antibiotics-treated pulmonary exacerbations during the trial. Excluded are exacerbations occurring during the first treatment cycle.	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)	The time to first change and usage of IV antibiotics to treat pulmonary exacerbations during the trial. Excluded are exacerbations occurring during the first treatment cycle.	From baseline to 28 weeks
Usage (Number of Antibiotic Treatments) of Antibiotic (Other Than Chronic Inhaled Antibiotics Already Started Prior to Trial or Oral Chronic Azithromycin)	Usage (number of antibiotic treatments per subject) of IV antibiotics to treat pulmonary exacerbations during the trial. Excluded are exacerbations occurring during the first treatment cycle.	From baseline to 28 weeks
Usage (Days) of Antibiotic (Other Than Chronic Inhaled Antibiotics Already Started Prior to Trial or Oral Chronic Azithromycin)	Usage (days) of IV antibiotics to treat pulmonary exacerbations during the trial. Excluded are exacerbations occurring during the first treatment cycle.	From baseline to 28 weeks
The Change From Baseline of Systemic Markers of Inflammation in Blood	This was assessed through scheduled blood sampling during the trial on three occasions. Both ITT and PP populations results presented. Samples were analyzed using validated analytical methods.	Change from baseline to Week 24
The Change From Screening of the Body Weight	This was assessed through serial weighing during the trial. Measurements performed at clinical sites using calibrated balances.	From screening to 28 weeks
The Change From Screening of the Body Mass Index (BMI)	This was assessed through serial weighing during the trial and calculation of BMI. Measurements performed at clinical sites using calibrated balances.	From screening to 28 weeks
The Overall Change From Screening of the Pseudomonas Aeruginosa Density (Colony Forming Units) in the Sputum	This was assessed through induced sputum (and spontaneously obtained during COVID-19 pandemic) on 3 occasions during the trial. Samples were analyzed at a central laboratory. An area under the curve (AUC from baseline to Week 24 inclusive) of colony forming unit/mL is calculated.	From screening to Week 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 was assessed through administration of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at four planned times during the trial. The CFQ-R respiratory sub-score (range 0-100) was extracted and analyzed. The Minimum Clinically Important Difference (MCID) for the respiratory sub-score is 4 units. A higher score means a better outcome.	From baseline to 24 weeks
The Change in Metabolipidomic Profile and in Markers of Oxidative Stress in Blood	This was assessed through serial blood sampling during the trial. Samples were analyzed using validated methods at specialized laboratories.	From baseline to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 IV antibiotics, this was to be assessed prior to- and after receiving an IV antibiotic course.	From baseline to 28 weeks
The Change From Baseline of Systemic Bone Formation and Resorption Biomarkers	This was assessed through blood sampling on 2 occasions during the trial at Baseline and Week 24.	Baseline and 24 weeks
The Change From Baseline of Bone Mineral Density	This was assessed through Lumbar spine bone mineral density measured on 2 occasions during the trial at Baseline and at Week 28 in a subset of sites and on a voluntary basis. Bone mineral density in g/cm2 is then normalized and expressed as a Z-score distribution according to age and gender. A Z-score of 0 represents the population mean for the age and gender category, a -1 value or +1 value means below or above the population mean bone mineral density for the age and gender category, but considered normal. A -2.5 value indicates secondary osteoporosis, a worse outcome.	Baseline and 28 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): November 5, 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 9, 2024
• Last Update Submitted That Met QC Criteria: October 4, 2024
• Last Verified: October 1, 2024

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