This study will evaluate the effect of a supratherapeutic dose of ALXN1840 on the heart rate (HR)-corrected QT interval (QTc) in healthy adult participants. Moxifloxacin will be used as the active control.
This is a randomized, 3-treatment, 3-period, 6-sequence, crossover, placebo- and active-controlled, double-blind for ALXN1840, open-label for moxifloxacin, in healthy adult participants. Participants will be domiciled in the clinic for 7 days during Treatment Period 1 and for 6 days during Treatment Period 2 and 3. A single oral dose of each treatment (ALXN1840, matching ALXN1840 placebo, or moxifloxacin) will be administered on Day 1 of each period following an overnight fast of at least 10 hours. There will be a minimum 14-day washout between study intervention administrations for each treatment period. Cardiodynamic, pharmacokinetic, and safety assessments will be performed at certain times during the study. An end-of-study visit will occur 14 days (±2 days) after the last dose.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
57
ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).
Placebo will be administered orally.
Moxifloxacin (400 milligrams) will be administered orally.
PPD Development, LP
Austin, Texas, United States
Placebo-corrected Change From Baseline For QTcF (ΔΔQTcF) for ALXN1840 Using The By-time Point Analysis
Twelve-lead electrocardiograms (ECGs) were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period. Change from baseline in the QT interval was corrected for heart rate using Fridericia's formula (ΔQTcF). ΔQTcF was based on a mixed-effects model for repeated measures (MMRM) with ΔQTcF as the dependent variable; period, sequence, time, treatment, and time-by-treatment interaction as fixed effects; and baseline QTc and sex as covariates. ΔΔQTc = LS mean ΔQTcF after ALXN1840 dosing minus LS mean ΔQTcF after placebo. If the upper bound of the confidence interval (CI) of ΔΔQTcF was \< 10 ms for all postdose time points, ALXN1840 was concluded to not have a significant effect on QT interval prolongation.
Time frame: Baseline (average of samples taken at -45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
ΔΔQTcF For Moxifloxacin Using The By-time Point Analysis
Assay sensitivity was evaluated using the by-time point analysis of the effect on ΔΔQTc of moxifloxacin. If ΔΔQTcF was larger than 5 ms at 1, 2, and 3 hours postdose, assay sensitivity was considered to be demonstrated.
Time frame: 1, 2, and 3 hours postdose at Day 1
Change From Baseline For Heart Rate (ΔHR)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Change From Baseline QT Interval Using Fridericia's Formula (ΔQTcF)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
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Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Change From Baseline PR Interval (ΔPR)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Change From Baseline QRS Interval (ΔQRS)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Placebo-corrected Change From Baseline Heart Rate (ΔΔHR)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period. Least square mean difference and its 90% CI were calculated based on MMRM with fixed effects for period, sequence, timepoint, treatment, time-by-treatment interaction as fixed effect and baseline value and sex as covariates.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Placebo-corrected Change From Baseline PR Interval (ΔΔPR)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Placebo-corrected Change From Baseline QRS Interval (ΔΔQRS)
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period. Least square mean difference and its 90% CI were calculated based on MMRM with fixed effects for period, sequence, timepoint, treatment, time-by-treatment interaction as fixed effect and baseline value and sex as covariates.
Time frame: Baseline (average of samples taken at 45, -30, and -15 minutes before dosing), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, and 24 (Day 2) hours postdose
Number of Participants With Treatment-emergent T-wave Morphology Abnormalities and U-waves
Twelve-lead ECGs were extracted from approximately 25-hour continuous (Holter) recordings on Day -1 of Treatment Period 1 and Days 1 and 2 in each treatment period.
Time frame: Day 1 (after dosing) through 24 hours postdose
ALXN1840 PK Parameter: Area Under The Concentration Versus Time Curve From Time 0 To The Last Quantifiable Concentration (AUC0-t) Of Total Molybdenum And Plasma Ultrafiltrate (PUF) Molybdenum Following a Single Oral Dose of ALXN1840
Blood samples for PK analysis of total molybdenum and PUF molybdenum were collected as close as possible to nominal time after completion of the ECG extraction period.
Time frame: Predose (0) to 96 hours post-dose
ALXN1840 PK Parameter: Maximum Observed Concentration (Cmax) Of Total Molybdenum And PUF Molybdenum Following a Single Oral Dose of ALXN1840
Blood samples for PK analysis of total molybdenum and PUF molybdenum were collected as close as possible to nominal time after completion of the ECG extraction period.
Time frame: Predose (0) to 96 hours post-dose
ALXN1840 PK Parameter: Time To Maximum Observed Concentration (Tmax) Of Total Molybdenum And PUF Molybdenum Following a Single Oral Dose of ALXN1840
Blood samples for PK analysis of total molybdenum and PUF molybdenum were collected as close as possible to nominal time after completion of the ECG extraction period.
Time frame: Pre-dose to 96 hours post-dose
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAE was an AE that started during or after the first dose, or started prior to the first dose and increased in severity after the first dose. A related TEAE was defined as having a reasonable possibility the study intervention caused the AE as assessed by the investigator. Serious AEs were defined as any untoward medical occurrence that met at least 1 of the following serious criteria: resulted in death, was life-threatening, required in-patient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, other medically important serious event.
Time frame: Day 1 (after dosing) through Day 70