A Study of the Cardiac Effects of ALXN1840 in Healthy Adults

Phase 1

Completed

Conditions: Healthy

Interventions: Drug: ALXN1840
Drug: Placebo
Drug: Moxifloxacin

Registration Number: NCT04560816

Lead Sponsor: Alexion Pharmaceuticals, Inc.

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 57

Inclusion Criteria

Nonsmoker.
Body weight at least 60 kilograms (kg) for males or 52 kg for females and body mass index ≥18.0 and ≤30.0 kg/meter squared.
Willing and able to follow protocol-specified contraception requirements.
Participant has no clinically significant history or presence of ECG findings.

Exclusion Criteria

History or presence of clinical and/or lab disorders.
Lymphoma, leukemia, or any malignancy within the past 5 years, or breast cancer within the past 10 years.
Participant has abnormal blood pressure, defined as a supine blood pressure <90/50 millimeters of mercury (mm Hg) or >140/90 mm Hg.
Serum potassium, calcium, or magnesium levels outside the normal range.
Serum copper and/or ceruloplasmin values below the lower limit of normal at Screening.
Female participant has hemoglobin <10.8 grams/deciliter (g/dL) and male participant has hemoglobin <12.5 g/dL.
Clinically significant multiple or severe allergies.
Alanine aminotransferase, aspartate aminotransferase, serum creatinine, or total bilirubin greater than upper limit of normal (with the exception of Gilbert's syndrome).

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment Sequence 2	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Moxifloxacin. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 3	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 1	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Placebo-matching ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 1	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Placebo-matching ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 2	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Moxifloxacin. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 2	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Moxifloxacin. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 3	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 3	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 4	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: Moxifloxacin. Period 3: ALXN1840.
Treatment Sequence 4	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: Moxifloxacin. Period 3: ALXN1840.
Treatment Sequence 5	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: ALXN1840. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 5	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: ALXN1840. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 6	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: Placebo-matching ALXN1840. Period 3: ALXN1840.
Treatment Sequence 6	Placebo	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: Placebo-matching ALXN1840. Period 3: ALXN1840.
Treatment Sequence 1	ALXN1840	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: ALXN1840. Period 2: Placebo-matching ALXN1840. Period 3: Moxifloxacin.
Treatment Sequence 5	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: ALXN1840. Period 3: Placebo-matching ALXN1840.
Treatment Sequence 4	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Placebo-matching ALXN1840. Period 2: Moxifloxacin. Period 3: ALXN1840.
Treatment Sequence 6	Moxifloxacin	On Day 1 of each period, participants will receive a single dose of the following study interventions: Period 1: Moxifloxacin. Period 2: Placebo-matching ALXN1840. Period 3: ALXN1840.

Primary Outcome Measures

Name	Time	Method
Placebo-corrected Change From Baseline For QTcF (ΔΔQTcF) for ALXN1840 Using The By-time Point Analysis	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	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.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline QRS Interval (ΔQRS)	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	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.
ΔΔQTcF For Moxifloxacin Using The By-time Point Analysis	1, 2, and 3 hours postdose at Day 1	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.
Placebo-corrected Change From Baseline QRS Interval (ΔΔQRS)	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	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.
ALXN1840 PK Parameter: Time To Maximum Observed Concentration (Tmax) Of Total Molybdenum And PUF Molybdenum Following a Single Oral Dose of ALXN1840	Pre-dose to 96 hours post-dose	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.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	Day 1 (after dosing) through Day 70	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.
Change From Baseline For Heart Rate (ΔHR)	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	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.
Change From Baseline QT Interval Using Fridericia's Formula (ΔQTcF)	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	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.
Change From Baseline PR Interval (ΔPR)	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	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.
Placebo-corrected Change From Baseline PR Interval (ΔΔPR)	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	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.
Number of Participants With Treatment-emergent T-wave Morphology Abnormalities and U-waves	Day 1 (after dosing) through 24 hours postdose	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.
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	Predose (0) to 96 hours post-dose	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.
ALXN1840 PK Parameter: Maximum Observed Concentration (Cmax) Of Total Molybdenum And PUF Molybdenum Following a Single Oral Dose of ALXN1840	Predose (0) to 96 hours post-dose	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.
Placebo-corrected Change From Baseline Heart Rate (ΔΔHR)	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	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.