A Study to Evaluate Multiple Doses of GLPG2222 in Adult Subjects With Cystic Fibrosis

• ClinicalTrials.gov Identifier: NCT03119649
• Recruitment Status: Completed
• First Posted: April 18, 2017
• Results First Posted: November 16, 2018
• Last Update Posted: November 16, 2018
• Sponsor: Galapagos NV
• Information provided by (Responsible Party): Galapagos NV

Tracking Information

• First Submitted Date: April 11, 2017
• First Posted Date: April 18, 2017
• Results First Submitted Date: October 19, 2018
• Results First Posted Date: November 16, 2018
• Last Update Posted Date: November 16, 2018
• Actual Study Start Date: March 18, 2017
• Actual Primary Completion Date: October 19, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 19, 2018)

Number of Participants With Treatment-Emergent Adverse Events [ Time Frame: First administration (Day 1) through Follow-up (Day 43) ]

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).

Original Primary Outcome Measures (submitted: April 17, 2017)

Safety and tolerability assessments determined by number of subjects with adverse events [ Time Frame: from baseline up to day 43 (final FU visit) ]

To evaluate the safety and tolerability of GLPG2222 as compared to placebo in terms of adverse events

Current Secondary Outcome Measures (submitted: October 19, 2018)

• Mean Change From Baseline in Sweat Chloride Concentration at Day 29 [ Time Frame: Prior to dosing on Days 1 and 29, or at early discontinuation ]
  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).
• Mean Change From Baseline in Percent (%) Predicted FEV1 (%FEV1) at Day 29 [ Time Frame: Predose and between 1 and 2 hours postdose on Days 1 and 29, or at early discontinuation ]
  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.
• Mean Change From Baseline in the Respiratory Domain of the Cystic Fibrosis Questionnaire-Revised (CFQ-R) at Day 29 [ Time Frame: Prior to dosing on Days 1 and 29, or at early discontinuation ]
  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.
• Mean Maximum Observed Plasma Concentration (Cmax; Nanograms Per Milliliter [mg/mL]) of GLPG2222 [ Time Frame: Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 ]
  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.
• Mean GLPG2222 Plasma Concentration Observed at Predose (Ctrough; ng/mL) [ Time Frame: Days 15 and 29 (predose) ]
  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.
• Median Time to Occurrence of GLPG2222 Cmax (Tmax; Hours [h]) [ Time Frame: Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 ]
  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.
• 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 [ Time Frame: Day 15 (predose and 0.5, 1, 2, 3, 4, 6, and 8 hours postdose) and prior to dosing on Day 29 ]
  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.

Original Secondary Outcome Measures (submitted: April 17, 2017)

• Change from baseline in Sweat chloride concentration [ Time Frame: from baseline up to day 29 ]
  To evaluate the effect of GLPG2222 on CFTR activity as compared to placebo
• Absolute change from baseline of FEV1 (L) for age, gender and height as assessed by spirometry [ Time Frame: from baseline up to day 29 ]
  To evaluate the effect of GLPG2222 on respiratory symptoms as compared to placebo
• Percent predicted FEV1 for age, gender and height as assessed by spirometry [ Time Frame: from baseline up to day 29 ]
  To evaluate the effect of GLPG2222 on respiratory symptoms as compared to placebo
• Change from baseline on the respiratory domain of Revised Cystic Fibrosis Questionnaire (CFQ-R) [ Time Frame: from baseline up to day 29 ]
  To evaluate the effect of GLPG2222 on respiratory symptoms as compared to placebo
• Cmax (maximum observed plasma concentration) of GLPG2222 [ Time Frame: pre-dose on day 15 and on day 29 ]
  To evaluate the PK of GLPG2222
• Cthrough (plasma concentration observed at pre-dose) [ Time Frame: pre-dose on day 15 and on day 29 ]
  To evaluate PK of GLPG2222
• tmax (time to the occurrence of Cmax) [ Time Frame: pre-dose on day 15 and on day 29 ]
  To evaluate PK of GLPG2222
• AUC(t) (area under the plasma concentration-time curve over the dosing interval) [ Time Frame: pre-dose on day 15 and on day 29 ]
  To evaluate PK of GLPG2222

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate Multiple Doses of GLPG2222 in Adult Subjects With Cystic Fibrosis
• Official Title: 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
• Brief Summary: 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Cystic Fibrosis

Intervention

• Drug: GLPG2222 50 mg
  Oral tablet(s) containing GLPG2222
• Drug: GLPG2222 100 mg
  Oral tablet(s) containing GLPG2222
• Drug: Placebo
  Matching oral tablet(s) containing placebo
• Drug: GLPG2222 200 mg
  Oral tablet(s) containing GLPG2222
• Drug: GLPG2222 400 mg
  Oral tablet(s) containing GLPG2222

Study Arms

• Experimental: Cohort A: GLPG2222 50 mg once daily (QD)
  Participants received a single GLPG2222 50 mg tablet and two matching placebo tablets orally, QD for 29 days.
  Interventions:

  • Drug: GLPG2222 50 mg
  • Drug: Placebo
• Experimental: Cohort A: GLPG2222 100 mg QD
  Participants received a single GLPG2222 100 mg tablet and two matching placebo tablets orally, QD for 29 days.
  Interventions:

  • Drug: GLPG2222 100 mg
  • Drug: Placebo
• Experimental: Cohort B: GLPG2222 200 mg QD
  Participants received two GLPG2222 100 mg tablets and one matching placebo tablet orally, QD for 29 days.
  Interventions:

  • Drug: Placebo
  • Drug: GLPG2222 200 mg
• Experimental: Cohort B: GLPG2222 400 mg QD
  Participants received two GLPG2222 150 mg tablets and one GLPG2222 100 mg tablet orally, QD for 29 days.
  Interventions:

  • Drug: Placebo
  • Drug: GLPG2222 400 mg
• Placebo Comparator: Cohort A Placebo
  Participants received three matching placebo tablets, orally, QD for 29 days.
  Intervention: Drug: Placebo
• Placebo Comparator: Cohort B Placebo
  Participants received three matching placebo tablets, orally, QD for 29 days.
  Intervention: Drug: Placebo

• Publications *: Bell SC, Barry PJ, De Boeck K, Drevinek P, Elborn JS, Plant BJ, Minić P, Van Braeckel E, Verhulst S, Muller K, Kanters D, Bellaire S, de Kock H, Geller DE, Conrath K, Van de Steen O, van der Ent K. CFTR activity is enhanced by the novel corrector GLPG2222, given with and without ivacaftor in two randomized trials. J Cyst Fibros. 2019 Sep;18(5):700-707. doi: 10.1016/j.jcf.2019.04.014. Epub 2019 May 3.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 17, 2017): 59
• Original Estimated Enrollment (submitted: April 17, 2017): 50
• Actual Study Completion Date: October 19, 2017
• Actual Primary Completion Date: October 19, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Male or female subject ≥ 18 years of age, on the day of signing the Informed Consent Form (ICF).
2. A confirmed clinical diagnosis of CF and homozygous for the F508del CFTR mutation
3. Weight ≥ 40 kg.
4. Stable concomitant treatment for at least 4 weeks (28 days) prior to baseline
5. Forced expiratory volume in 1 second (FEV1) ≥ 40% of predicted normal for age, gender and height at screening

Exclusion Criteria:

1. 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.
2. Unstable pulmonary status or respiratory tract infection requiring a change in therapy within 4 weeks of baseline.
3. Need for supplemental oxygen during the day, and >2 liters per minute (LPM) while sleeping.
4. Use of CFTR modulator therapy (e.g. lumacaftor or ivacaftor) within 4 weeks prior to the first study drug administration.
5. History of hepatic cirrhosis with portal hypertension.
6. 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)
7. Estimated creatinine clearance < 60 mL/min using the Cockcroft-Gault formula at screening.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 99 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Netherlands, Serbia, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03119649
• Other Study ID Numbers: GLPG2222-CL-202
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Galapagos NV
• Study Sponsor: Galapagos NV
• Collaborators: Not Provided

Investigators

• Study Director: Olivier Van Steen, MD, MBA; Galapagos NV

• PRS Account: Galapagos NV
• Verification Date: October 2018