GLPG2737 on Top of Orkambi in Subjects With Cystic Fibrosis

Study Overview
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Brief Summary
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This is a Phase IIa, multi-center, randomized, double-blind, placebo-controlled, parallel-group study to evaluate GLPG2737 administered orally b.i.d. for 28 days to adult male and female subjects with a confirmed diagnosis of cystic fibrosis homozygous for the F508del CFTR mutation and on stable treatment with Orkambi.

Official Title
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A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate GLPG2737 in Orkambi-treated Subjects With Cystic Fibrosis Homozygous for the F508del Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: GLPG2737
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female subject ≥18 years of age on the day of signing the ICF. A confirmed clinical diagnosis of CF and homozygous for the F508del CFTR mutation. Stable intake of physician prescribed Orkambi (lumacaftor 400 mg/ivacaftor 250 mg b.i.d.) for at least 12 weeks prior to the first study drug administration, and planned continuation of Orkambi for the duration of the study. FEV1 ≥40% of predicted normal for age, gender and height at screening (pre- or postbronchodilator). Sweat chloride concentration ≥60 mmol/L at screening. Exclusion Criteria: History of serious allergic reaction to any drug as determined by the investigator (e.g., anaphylaxis requiring hospitalization) and/or known sensitivity to any component of the study drug. History of clinically meaningful unstable or uncontrolled chronic disease that makes the subject unsuitable for inclusion in the study in the opinion of the investigator. Unstable pulmonary status or respiratory tract infection (including rhinosinusitis) requiring a change in therapy within 4 weeks prior to the first study drug administration. History of hepatic cirrhosis with portal hypertension (e.g.,signs/symptoms of splenomegaly, esophageal varices, etc.). Abnormal liver function test at screening, defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/or alkaline phosphatase and/or gammaglutamyl transferase (GGT) ≥3 x the upper limit of normal (ULN), and/or total bilirubin ≥1.5 x the ULN at screening.

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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GLPG2737<br>GLPG2737 will be provided as capsules for oral use. | Drug: GLPG2737<br>* GLPG2737 oral capsules administered twice daily for 28 days on top of Orkambi.<br>|
| Placebo Comparator: Placebo<br>Placebo will be provided as capsules for oral use. | Drug: Placebo<br>* Placebo oral capsules administered twice daily for 28 days on top of Orkambi.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in sweat chloride concentration compared to placebo | To assess Change from baseline in sweat chloride concentration compared to placebo. | Between day 1 pre-morning dose and Day 28. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change versus placebo in the proportion of subjects with adverse events. | To assess safety and tolerability by the number and percentage of subjects with adverse events. | Between Day 1 and 3 weeks after the last dose. | 
| Change from baseline in sweat chloride concentration. | To assess the change from baseline in sweat chloride concentration. | From baseline (pre-morning dose on Day 1) through 28 days. | 
| Change in percent predicted forced expiratory volume in 1 second (FEV1). | To assess the change from baseline in percent predicted forced expiratory volume in 1 second (FEV1). | From baseline (pre-morning dose on Day 1) through 28 days. | 
| Change in the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R). | To assess the change from baseline in the respiratory domain of the cystic fibrosis questionnaire-revised (CFQ-R). | From baseline (pre-morning dose on Day 1) through 28 days. | 
| Maximum observed plasma concentration of GLPG2737 (Cmax) | To characterize the PK of GLPG2737 and its active metabolite, ivacaftor, and lumacaftor. | Between day 1 pre-dose and day 14. | 
| Area under the plasma concentration-time curve from time zero until 8 hours (AUC0-8h) post-dose calculated by the linear up - logarithmic down trapezoidal rule (on Day 14) | To characterize the PK of GLPG2737 and its active metabolite G1125498 (M4), ivacaftor, and lumacaftor. | Between day 1 pre-dose and day 14. | 
| Trough plasma concentration observed at the end of the dosing interval (Ctrough). | To characterize the PK of GLPG2737 and its active metabolite G1125498 (M4), ivacaftor, and lumacaftor. | Between day 1 pre-dose and day 28. |