A Study to Evaluate Multiple Doses of GLPG2222 in Adult 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 4 different doses of GLPG2222 administered for 4 weeks to adult subjects with a confirmed diagnosis of CF and homozygous for the F508del Cystic Fibrosis Transmembrane conductance Regulator (CFTR) mutation.

Official Title
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A Phase IIa, Randomized, Double-blind, Placebo-controlled Study to Evaluate Multiple Doses of GLPG2222 in Subjects With Cystic Fibrosis Who Are Homozygous for the F508del Mutation

Conditions
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Cystic Fibrosis

Intervention / Treatment
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* Drug: GLPG2222 50 mg
* Drug: GLPG2222 100 mg
* Drug: Placebo
* Drug: GLPG2222 200 mg
* Drug: GLPG2222 400 mg


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 Informed Consent Form (ICF). A confirmed clinical diagnosis of CF and homozygous for the F508del CFTR mutation Weight ≥ 40 kg. Stable concomitant treatment for at least 4 weeks (28 days) prior to baseline Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted normal for age, gender and height at screening Exclusion Criteria: 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 requiring a change in therapy within 4 weeks of baseline. Need for supplemental oxygen during the day, and >2 liters per minute (LPM) while sleeping. Use of CFTR modulator therapy (e.g. lumacaftor or ivacaftor) within 4 weeks prior to the first study drug administration. History of hepatic cirrhosis with portal hypertension. Abnormal liver function test at screening; defined as aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) and/ or alkaline phosphatase and/or gamma-glutamyl transferase (GGT) ≥ 3x the upper limit of normal (ULN); and/or total bilirubin (>1.5 times ULN) Estimated creatinine clearance < 60 mL/min using the Cockcroft-Gault formula at screening.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Cohort A: GLPG2222 50 mg once daily (QD)<br>Participants received a single GLPG2222 50 mg tablet and two matching placebo tablets orally, QD for 29 days. | Drug: GLPG2222 50 mg<br>* Oral tablet(s) containing GLPG2222<br>Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>|
| Experimental: Cohort A: GLPG2222 100 mg QD<br>Participants received a single GLPG2222 100 mg tablet and two matching placebo tablets orally, QD for 29 days. | Drug: GLPG2222 100 mg<br>* Oral tablet(s) containing GLPG2222<br>Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>|
| Experimental: Cohort B: GLPG2222 200 mg QD<br>Participants received two GLPG2222 100 mg tablets and one matching placebo tablet orally, QD for 29 days. | Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>Drug: GLPG2222 200 mg<br>* Oral tablet(s) containing GLPG2222<br>|
| Experimental: Cohort B: GLPG2222 400 mg QD<br>Participants received two GLPG2222 150 mg tablets and one GLPG2222 100 mg tablet orally, QD for 29 days. | Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>Drug: GLPG2222 400 mg<br>* Oral tablet(s) containing GLPG2222<br>|
| Placebo Comparator: Cohort A Placebo<br>Participants received three matching placebo tablets, orally, QD for 29 days. | Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>|
| Placebo Comparator: Cohort B Placebo<br>Participants received three matching placebo tablets, orally, QD for 29 days. | Drug: Placebo<br>* Matching oral tablet(s) containing placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events | Number of participants with any treatment-emergent adverse events (TEAEs) and serious or treatment-related TEAEs, as well as number of patients with TEAEs by worst intensity reported (mild, moderate, or severe). | First administration (Day 1) through Follow-up (Day 43) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change From Baseline in Sweat Chloride Concentration at Day 29 | Two sweat collections, one from each arm, were obtained. Mean sweat chloride concentration was determined from both arms and measured as millimoles per liter (mmol/L). Baseline was defined as the predose value on Day 1 (or the last non-missing predose measurement). | Prior to dosing on Days 1 and 29, or at early discontinuation | 
| Mean Change From Baseline in Percent (%) Predicted FEV1 (%FEV1) at Day 29 | Percent predicted FEV1 for age, gender, and height was determined from standardized spirometry assessments and estimated using the 2012 Global Lungs Initiative equation. Baseline was defined as the last non-missing predose assessment on Day 1. | Predose and between 1 and 2 hours postdose on Days 1 and 29, or at early discontinuation | 
| Mean Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at Day 29 | The CFQ-R is a validated participant-reported outcome measuring health-related quality of life for participants with cystic fibrosis. The respiratory domain assessed respiratory symptoms (for example, coughing, congestion, wheezing), derived from Questions 40, 41, 42, 45, and 46 if at least 50% of the questions had non-missing data. The scale score ranged from 0-100; higher scores indicated fewer symptoms and better health-related quality of life with a negative change indicating a worsening of symptoms. A change of 4 is considered clinically relevant. | Prior to dosing on Days 1 and 29, or at early discontinuation | 
| Mean Maximum Observed Plasma Concentration (Cmax; Nanograms Per Milliliter [mg/mL]) of GLPG2222 | Maximum concentration of GLPG2222 after multiple dosing (ng/ML), obtained directly from the observed concentration versus time data. All pharmacokinetic (PK) parameters were determined from Day 15; Day 29 data were determined if the participant was not available for full PK profiling on Day 15. | Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 | 
| Mean GLPG2222 Plasma Concentration Observed at Predose (Ctrough; ng/mL) | Plasma concentration of GLPG2222 observed at pre-dose (ng/mL), obtained directly from the observed concentration versus time data. Ctrough was calculated using both Day 15 and Day 29 PK data. | Days 15 and 29 (predose) | 
| Median Time to Occurrence of GLPG2222 Cmax (Tmax; Hours [h]) | Time of occurrence of maximum concentration of GLPG2222 after multiple dosing (h), obtained directly from the observed concentration versus time data. All PK parameters were determined from Day 15; Day 29 data were determined if the participant was not available for full PK profiling on Day 15. | Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 | 
| Mean Area Under the Concentration-Time Curve From Time 0 up to 24 Hours Following Multiple Dosing (AUC[0-t]; ng.h/mL) of GLPG2222 | Area under the concentration-time curve from time 0 up to 24 hours following multiple dosing (ng.h/mL), calculated by linear up/log down trapezoidal summation. All PK parameters were determined from Day 15; Day 29 data were determined if the participant was not available for full PK profiling on Day 15. | Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 |