This is a Phase 1, single-center, double-blind, randomized, placebo- and positive controlled, double-dummy, parallel-group, repeated-dose study with a nested cross-over comparison between moxifloxacin and placebo to evaluate the effect of MD1003 on cardiac repolarization in healthy adult subjects. The planned enrollment is approximately 64 subjects randomized in a ratio of 1:1 to 2main groups. Subjects in Group B will be further randomized to Subgroups B1 and B2 in a ratio of 1:1.
This study is designed as a definitive evaluation of the potential of MD1003 and its major metabolites to have a threshold effect on cardiac repolarization, as detected by QT/QTc prolongation. The design is aligned with the recommendations for evaluation of QT/QTc interval prolongation outlined in the International Council for Harmonization (ICH) E14 guidance. This is a Phase 1, single-center, double-blind, randomized, placebo- and positive controlled, double-dummy, parallel-group, repeated-dose study with a nested cross-over comparison between moxifloxacin and placebo to evaluate the effect of MD1003 on cardiac repolarization in healthy adult subjects. A total of 64 subjects will be enrolled in the clinical study according to the inclusion/exclusion criteria. The study consists of two main groups with 32 subjects per dose group. All subjects will receive placebo for MD1003 on Day -1. Subjects in Group A will receive MD1003 (biotin) 1200 mg and placebo for moxifloxacin on Day 1, MD1003 (biotin) 1200 mg from Day 2 through Day 8 and placebo for moxifloxacin on Day 9. Subjects in Group B will be further randomized to Subgroup B1 (16 subjects) receiving moxifloxacin 400 mg and placebo for MD1003 on Day 1, placebo for MD1003 from Day 2 through Day 8 and placebo for moxifloxacin on Day 9. Subgroup B2 (16 subjects) will receive placebo for moxifloxacin and placebo for MD1003 on Day 1, placebo for MD1003 from Day 2 through Day 8 and moxifloxacin 400 mg on Day 9.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
QUADRUPLE
Enrollment
64
Group A: Daily dose of 1200 mg of MD1003 from Day 1 to Day 8
Group B1: Moxifloxacin 400 mg on Day 1 Group B2: Moxifloxacin 400 mg on Day 9
Group A: Placebo for MD1003 on Day -1 Group B1: Placebo for MD1003 on Day -1 Group B2: Placebo for MD1003 on Day -1
Parexel Early Phase Clinical Unit London
London, Middlesex, United Kingdom
RECRUITINGChange from baseline QTcF (ΔQTcF) on Day 8 (after 8 days of 1200 mg MD1003)
Replicate electrocardiograms (ECGs) (10 ECG replicates) for the determination of ΔQTc interval will be extracted from the continuous digital 12-lead ECG recording in the 5 minutes prior to dosing and then at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D-1 and D8
Time frame: 9 days
Placebo-corrected change from baseline QTcF (ΔΔQTcF) on Day 8 (after 8 days of 1200 mg MD1003)
Replicate electrocardiograms (ECGs) (10 ECG replicates) for the determination of ΔΔQTc interval will be extracted from the continuous digital 12-lead ECG recording in the 5 minutes prior to dosing and then at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D-1 and D8
Time frame: 9 days
Change from baseline of Heart Rate (ΔHR) on Day 8 (after 8 days of 1200 mg MD1003)
Replicate electrocardiograms (ECGs) (10 ECG replicates) for the determination of ΔHR interval will be extracted from the continuous digital 12-lead ECG recording in the 5 minutes prior to dosing and then at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D-1 and D8
Time frame: 9 days
Placebo-corrected, change from baseline of Heart Rate (ΔΔHR) on Day 8 (after 8 days of 1200 mg MD1003)
Replicate electrocardiograms (ECGs) (10 ECG replicates) for the determination of ΔΔHR interval will be extracted from the continuous digital 12-lead ECG recording in the 5 minutes prior to dosing and then at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D-1 and D8
Time frame: 9 days
Change from baseline of Pulse Rate (ΔPR) on Day 8 (after 8 days of 1200 mg MD1003)
Measurement of PR will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
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Group A: Placebo for moxifloxacin on Day 1 and Day 9 Group B1: Placebo for moxifloxacin on Day 9 Group B2: Placebo for moxifloxacin on Day 1
Time frame: 8 days
Placebo-corrected, change from baseline of Pulse Rate (ΔΔPR) on Day 8 (after 8 days of 1200 mg MD1003)
Measurement of PR will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
Time frame: 8 days
Change from baseline of QRS interval (ΔQRS) on Day 8 (after 8 days of 1200 mg MD1003)
Measurement of QRS interval will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
Time frame: 8 days
Placebo-corrected, change from baseline of QRS interval (ΔΔQRS) on Day 8 (after 8 days of 1200 mg MD1003)
Measurement of QRS interval will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
Time frame: 8 days
T-wave morphology
Frequency of treatment emergent changes in T-wave morphology. Measurement of T-wave morphology will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
Time frame: 8 days
U-waves presence
Frequency of treatment emergent changes in U-waves presence. Measurement of U-waves presence will be performed manually in 3 of the 9 ECG replicates at each timepoint at 0.5, 1, 2, 3, 4, 8, 12 and 24 hours post-dose on D1 and D8
Time frame: 8 days
Maximum plasma concentrations (Cmax) of MD1003 will be measured at D1 and D8 post-dose (after 8 days of dosing of 1200mg of MD1003)
The measured individual plasma concentration at pre-dose then at 0.5, 1, 2, 3, 4, 8,12, 24 hours (D1 and D8) post-dose will be used to directly obtain Cmax. Unit: ng/ml.
Time frame: 8 days
Area under the curve (AUC max) of MD1003 will be measured at D1 and D8 post-dose (after 8 days of dosing of 1200mg of MD1003)
AUC max at pre-dose then at 0.5, 1, 2, 3, 4, 8,12, 24 hours (D1 and D8) post-dose will be used to directly obtain AUC max. Unit: ng.h/ml
Time frame: 8 days
Time for maximum plasma concentration (tmax) of MD1003 will be determined directly from the concentration-time profile
tmax will be determined directly from the concentration-time profile. Unit: hour
Time frame: 8 days