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Completed

NCT Number: NCT03265288

Study 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.

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Key information

Conditions

Cystic Fibrosis Congenital, Hereditary, and Neonatal Diseases and Abnormalities Digestive System Diseases Genetic Diseases, Inborn Infant, Newborn, Diseases Inflammation Lung Diseases Pancreatic Diseases Pathologic Processes Pathological Conditions, Signs and Symptoms Respiratory Tract Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Respiratory Medicine, John Hunter Hospital, New Lambton Heights, New South Wales, Australia

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About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

LAU-7b

Drug

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

Placebo oral capsule

Drug

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

Primary outcomes

  1. Absolute Change in Percent Predicted Forced Expiratory Volume in 1 Second (FEV1%)

    Time frame: From baseline to 24 weeks

    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.

  2. Summary of Treatment Emergent Adverse Events With ≥ 10% Incidence

    Time frame: From Baseline to 28 weeks

    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

Secondary outcomes

  1. The Proportion of Patients Achieving Normalization of the Arachidonic Acid, Docosahexaenoic Acid and Their Ratio in Phospholipids

    Time frame: From baseline to 28 weeks

    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.

  2. The Absolute Change in FEV1 Percent Predicted at 3, 7, 11, 15, 24 and 28 Weeks Into the Trial

    Time frame: From baseline to 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.

  3. The Relative (%) Change in FEV1 Percent Predicted at 3, 7, 11, 15, 24 and 28 Weeks Into the Trial

    Time frame: From baseline to 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.

  4. The Time to First Protocol-Defined Pulmonary Exacerbation

    Time frame: From baseline to 28 weeks

    Reports of IV antibiotics-treated pulmonary exacerbations during the trial that meet the Fuch's criteria and after the first treatment cycle.

  5. The Number Per Subject of Protocol-Defined Pulmonary Exacerbations (PEx) During the Trial

    Time frame: From baseline to 28 weeks

    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.

  6. The Time to First Change and Usage of Antibiotic (Other Than Chronic Inhaled Antibiotics Already Started Prior to Trial or Oral Chronic Azithromycin)

    Time frame: From baseline to 28 weeks

    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.

  7. Usage (Number of Antibiotic Treatments) of Antibiotic (Other Than Chronic Inhaled Antibiotics Already Started Prior to Trial or Oral Chronic Azithromycin)

    Time frame: From baseline to 28 weeks

    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.

  8. Usage (Days) of Antibiotic (Other Than Chronic Inhaled Antibiotics Already Started Prior to Trial or Oral Chronic Azithromycin)

    Time frame: From baseline to 28 weeks

    Usage (days) of IV antibiotics to treat pulmonary exacerbations during the trial. Excluded are exacerbations occurring during the first treatment cycle.

  9. The Change From Baseline of Systemic Markers of Inflammation in Blood

    Time frame: Change from baseline to Week 24

    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.

  10. The Change From Screening of the Body Weight

    Time frame: From screening to 28 weeks

    This was assessed through serial weighing during the trial. Measurements performed at clinical sites using calibrated balances.

  11. The Change From Screening of the Body Mass Index (BMI)

    Time frame: From screening to 28 weeks

    This was assessed through serial weighing during the trial and calculation of BMI. Measurements performed at clinical sites using calibrated balances.

  12. The Overall Change From Screening of the Pseudomonas Aeruginosa Density (Colony Forming Units) in the Sputum

    Time frame: From screening to Week 24

    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.

  13. The Impact (From Baseline) on Overall Health, Daily Life, Perceived Well-being and Symptoms Measured With the Cystic Fibrosis Questionnaire-Revised (CFQ-R)

    Time frame: From baseline to 24 weeks

    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.

  14. The Change in Metabolipidomic Profile and in Markers of Oxidative Stress in Blood

    Time frame: From baseline to 24 weeks

    This was assessed through serial blood sampling during the trial. Samples were analyzed using validated methods at specialized laboratories.

Other outcomes

  1. The Change in Metabolipidomic Profile in Blood, the Systemic Markers of Inflammation in Blood, the FEV1, the Body Weight and Calculated BMI

    Time frame: From baseline to 28 weeks

    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.

  2. The Change From Baseline of Systemic Bone Formation and Resorption Biomarkers

    Time frame: Baseline and 24 weeks

    This was assessed through blood sampling on 2 occasions during the trial at Baseline and Week 24.

  3. The Change From Baseline of Bone Mineral Density

    Time frame: Baseline and 28 weeks

    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.

Sponsors and collaborators

Lead sponsor

Laurent Pharmaceuticals Inc.

Industry

Collaborators

  • Cystic Fibrosis Foundation

Registry information

Official study title

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

Acronym: APPLAUD

Important dates

Study start
2018
Primary completion
2021
Study completion
2021
First posted
Aug 29, 2017
Registry last updated
Oct 9, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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