NCT03265288: APPLAUD

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

Completed Phase 2 Results posted Last updated 9 October 2024

What this trial tests

Phase 2 trial testing LAU-7b in Cystic Fibrosis in 166 participants. Completed in 15 September 2021.

Timeline

5 November 2018

Primary endpoint
15 September 2021

15 September 2021

Quick facts

Lead sponsor	Laurent Pharmaceuticals Inc.
Phase	Phase 2
Status	Completed
Study type	INTERVENTIONAL
Allocation	randomized
Design	parallel
Masking	quadruple
Primary purpose	treatment
Enrollment	166
Start date	5 November 2018
Primary completion	15 September 2021
Estimated completion	15 September 2021
Sites	40 locations across Canada, United States, Australia

Drugs / interventions tested

• LAU-7b — full drug profile →
• Placebo oral capsule

Conditions studied

• Cystic Fibrosis — all drugs for Cystic Fibrosis →

Sponsor

Laurent Pharmaceuticals Inc. — full company profile →

Who can join

18 and older, any sex, with Cystic Fibrosis. Patients with the condition only — healthy volunteers not accepted.

Results — posted to ClinicalTrials.gov

Per-arm endpoint measurements with 95% confidence intervals where reported. Source: trial results section.

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

ITT population at Week 24

Group	Value	95% CI
LAU-7b	-1.1774	-2.5038 – 0.1490
Placebo	-1.9489	-3.2241 – -0.6738

ITT population through Week 24

Group	Value	95% CI
LAU-7b	-0.5417	-1.5226 – 0.4392
Placebo	-1.5470	-2.5304 – -0.5637

PP population through Week 24

Group	Value	95% CI
LAU-7b	-0.3374	-1.4987 – 0.8239
Placebo	-1.5632	-2.7333 – -0.3930

ITT subgroup >=70% ppFEV1, at Week 24

Group	Value	95% CI
LAU-7b	-1.4059	-3.5506 – 0.7388
Placebo	-4.0687	-6.1289 – -2.0085

ITT subgroup on CFTR modulators, at Week 24

Group	Value	95% CI
LAU-7b	-0.3336	-2.2467 – 1.5795
Placebo	-1.7247	-3.2954 – -0.1539

ITT subgroup on ETI, at Week 24

Group	Value	95% CI
LAU-7b	-0.7406	-3.7472 – 2.2659
Placebo	-1.8709	-4.1669 – 0.4252

Summary of Treatment Emergent Adverse Events With ≥ 10% Incidence Primary · 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

Subjects with at least one TEAE with ≥10% incidence

Group	Value	95% CI
LAU-7b	74
Placebo	64

Mild highest reported severity

Group	Value	95% CI
LAU-7b	22
Placebo	27

Moderate highest reported severity

Group	Value	95% CI
LAU-7b	45
Placebo	43

Severe highest reported severity

Group	Value	95% CI
LAU-7b	13
Placebo	7

Life threatening

Group	Value	95% CI
LAU-7b	0
Placebo	0

Infective pulmonary exacerbation of cystic fibrosis

Group	Value	95% CI
LAU-7b	37
Placebo	32

Cough

Group	Value	95% CI
LAU-7b	23
Placebo	24

Delayed dark adaptation

Group	Value	95% CI
LAU-7b	22
Placebo	4

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

Arachidonic acid (AA) normalization

Group	Value	95% CI
LAU-7b	15
Placebo	25

Docosahexaenoic acid (DHA) normalization

Group	Value	95% CI
LAU-7b	16
Placebo	18

AA/DHA ratio normalization

Group	Value	95% CI
LAU-7b	25
Placebo	23

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

Absolute change at Week 3

Group	Value	95% CI
LAU-7b	-0.243	± 5.110
Placebo	-1.494	± 4.537

Absolute change at Week 7

Group	Value	95% CI
LAU-7b	0.280	± 4.689
Placebo	-0.888	± 3.968

Absolute change at Week 11

Group	Value	95% CI
LAU-7b	-0.309	± 4.268
Placebo	-0.871	± 4.133

Absolute change at Week 15

Group	Value	95% CI
LAU-7b	-0.508	± 5.100
Placebo	-1.591	± 4.389

Absolute change at Week 24

Group	Value	95% CI
LAU-7b	-1.024	± 4.286
Placebo	-1.759	± 4.533

Absolute change at Week 28

Group	Value	95% CI
LAU-7b	-1.539	± 4.808
Placebo	-1.413	± 4.457

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

Relative (%) change at Week 3

Group	Value	95% CI
LAU-7b	-1.188	± 8.632
Placebo	-2.341	± 7.289

Relative (%) change at Week 7

Group	Value	95% CI
LAU-7b	0.561	± 8.348
Placebo	-1.550	± 6.829

Relative (%) change at Week 11

Group	Value	95% CI
LAU-7b	-0.213	± 7.124
Placebo	-1.277	± 7.120

Relative (%) change at Week 15

Group	Value	95% CI
LAU-7b	-0.924	± 8.963
Placebo	-2.745	± 7.425

Relative (%) change at Week 24

Group	Value	95% CI
LAU-7b	-1.450	± 6.966
Placebo	-2.652	± 7.742

Relative (%) change at Week 28

Group	Value	95% CI
LAU-7b	-2.388	± 8.275
Placebo	-2.085	± 7.525

The Time to First Protocol-Defined Pulmonary Exacerbation Secondary · 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.

Group	Value	95% CI
LAU-7b	NA	NA – NA
Placebo	NA	NA – NA

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

Protocol-Defined IV-treated PEx events per subject

Group	Value	95% CI
LAU-7b	0.16	± 0.398
Placebo	0.10	± 0.335

All IV-treated PEx events per subject

Group	Value	95% CI
LAU-7b	0.24	± 0.458
Placebo	0.18	± 0.566

All IV- or Oral antibiotics-treated PEx events per subject

Group	Value	95% CI
LAU-7b	0.53	± 0.721
Placebo	0.47	± 0.817

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

Group	Value	95% CI
LAU-7b	NA	NA – NA
Placebo	NA	NA – NA

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

Group	Value	95% CI
LAU-7b	0.53	± 1.09
Placebo	0.41	± 1.32

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

Group	Value	95% CI
LAU-7b	3.8	± 7.50
Placebo	3.5	± 14.94

The Change From Baseline of Systemic Markers of Inflammation in Blood Secondary · 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.

Absolute change from baseline of C-reactive protein at Week 24 ITT Population

Group	Value	95% CI
LAU-7b	-1.197	± 7.904
Placebo	2.532	± 10.650

Absolute change from baseline of calprotectin at Week 24, ITT population

Group	Value	95% CI
LAU-7b	-27	± 962
Placebo	478	± 2088

Absolute change from baseline of C-reactive protein at Week 24 PP Population

Group	Value	95% CI
LAU-7b	-1.216	± 7.987
Placebo	2.532	± 10.654

Absolute change from baseline of calprotectin at Week 24, PP population

Group	Value	95% CI
LAU-7b	-18	± 970
Placebo	478	± 2088

The Change From Screening of the Body Weight Secondary · From screening to 28 weeks

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

Group	Value	95% CI
LAU-7b	-0.43	± 2.41
Placebo	0.14	± 1.96

Adverse events — posted to ClinicalTrials.gov

Time frame: 28 weeks. Reporting threshold: 5%. Adverse-event reports describe events observed during the trial — not all are caused by the drug.

LAU-7b

Serious: 20/83 (24%)

Deaths: 0/83

Placebo

Serious: 15/83 (18%)

Deaths: 0/83

Serious adverse events (11 terms)

Reaction	System	LAU-7b	Placebo
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	—	—
Distal intestinal obstruction syndrome	Gastrointestinal disorders	—	—
Appendicitis	Infections and infestations	—	—
Hemoptysis	Respiratory, thoracic and mediastinal disorders	—	—
Loss of visual contrast sensitivity	Eye disorders	—	—
Constipation	Gastrointestinal disorders	—	—
Small intestinal obstruction	Gastrointestinal disorders	—	—
Influenza	Infections and infestations	—	—
Pneumonia staphylococcal	Infections and infestations	—	—
Pneumonia	Infections and infestations	—	—
Traumatic intracranial hemorrhage	Injury, poisoning and procedural complications	—	—

Other adverse events (31 terms — click to expand)

Reaction	System	LAU-7b	Placebo
Cough	Respiratory, thoracic and mediastinal disorders	—	—
Delayed dark adaptation	Eye disorders	—	—
Infective pulmonary exacerbation of cystic fibrosis	Infections and infestations	—	—
Night blindness	Eye disorders	—	—
Headache	Nervous system disorders	—	—
Upper respiratory tract infection	Infections and infestations	—	—
Hemoptysis	Respiratory, thoracic and mediastinal disorders	—	—
Sputum increased	Respiratory, thoracic and mediastinal disorders	—	—
Diarrhea	Gastrointestinal disorders	—	—
Dyspnea	Respiratory, thoracic and mediastinal disorders	—	—
Delayed light adaptation	Eye disorders	—	—
Fatigue	General disorders	—	—
Glare	Eye disorders	—	—
Visual impairment	Eye disorders	—	—
Oropharyngeal pain	Respiratory, thoracic and mediastinal disorders	—	—
Abdominal pain	Gastrointestinal disorders	—	—
Rash	Skin and subcutaneous tissue disorders	—	—
Xanthopsia	Eye disorders	—	—
Nausea	Gastrointestinal disorders	—	—
Insomnia	Psychiatric disorders	—	—
Photophobia	Eye disorders	—	—
Pyrexia	General disorders	—	—
Nasopharyngitis	Infections and infestations	—	—
Glucose urine present	Investigations	—	—
Acne	Skin and subcutaneous tissue disorders	—	—
Chest discomfort	General disorders	—	—
Blood glucose increased	Investigations	—	—
Arthralgia	Musculoskeletal and connective tissue disorders	—	—
Nasal congestion	Respiratory, thoracic and mediastinal disorders	—	—
Productive cough	Respiratory, thoracic and mediastinal disorders	—	—
Pruritus	Skin and subcutaneous tissue disorders	—	—

Most-reported serious reactions: Infective pulmonary exacerbation of cystic fibrosis, Distal intestinal obstruction syndrome, Appendicitis, Hemoptysis, Loss of visual contrast sensitivity, Constipation, Small intestinal obstruction, Influenza.

Data from ClinicalTrials.gov NCT03265288 adverse events section.

Sponsor's own 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.

Publications & conference data

8 peer-reviewed publications reference this trial (live from Europe PMC):

1. Targeting fibrosis, mechanisms and cilinical trials.
   Zhao M, Wang L, Wang M, Zhou S, et al · · 2022 · cited 352× · PMID 35773269 · DOI 10.1038/s41392-022-01070-3
2. Agonists that stimulate secretion promote the recruitment of CFTR into membrane lipid microdomains.
   Abu-Arish A, Pandžić E, Kim D, Tseng HW, et al · · 2019 · cited 22× · PMID 31048413 · DOI 10.1085/jgp.201812143
3. Treatment of Pulmonary Disease of Cystic Fibrosis: A Comprehensive Review.
   Girón Moreno RM, García-Clemente M, Diab-Cáceres L, Martínez-Vergara A, et al · · 2021 · cited 20× · PMID 33922413 · DOI 10.3390/antibiotics10050486
4. Novel therapeutic approaches for the management of cystic fibrosis.
   Jaques R, Shakeel A, Hoyle C. · · 2020 · cited 13× · PMID 33282281 · DOI 10.4081/mrm.2020.690
5. The role of essential fatty acids in cystic fibrosis and normalizing effect of fenretinide.
   Garić D, Dumut DC, Shah J, De Sanctis JB, et al · · 2020 · cited 12× · PMID 32394023 · DOI 10.1007/s00018-020-03530-x
6. Lights and Shadows in the Use of Mesenchymal Stem Cells in Lung Inflammation, a Poorly Investigated Topic in Cystic Fibrosis.
   Caretti A, Peli V, Colombo M, Zulueta A. · · 2019 · cited 12× · PMID 31861724 · DOI 10.3390/cells9010020
7. Druggable Sphingolipid Pathways: Experimental Models and Clinical Opportunities.
   Blaho VA. · · 2020 · cited 9× · PMID 32894509 · DOI 10.1007/978-3-030-50621-6_6
8. Treatment With LAU-7b Complements CFTR Modulator Therapy by Improving Lung Physiology and Normalizing Lipid Imbalance Associated With CF Lung Disease.
   Centorame A, Dumut DC, Youssef M, Ondra M, et al · · 2022 · cited 3× · PMID 35668939 · DOI 10.3389/fphar.2022.876842