A Study of the Cardiac Effects of ALXN1840 in Healthy Adults

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Randomized, 3-Treatment, 3-Period, 6-Sequence, Crossover, Placebo- and Active-Controlled, Double-Blind for ALXN1840 (Open-Label for Moxifloxacin) Thorough QT/QTc Study to Evaluate ALXN1840 on Cardiac Repolarization in Healthy Adults

Conditions
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Healthy

Intervention / Treatment
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* Drug: ALXN1840
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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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).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: This will be a 3-treatment, 3-period, 6-sequence, crossover study in healthy adults.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment Sequence 1<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|
| Experimental: Treatment Sequence 2<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|
| Experimental: Treatment Sequence 3<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|
| Experimental: Treatment Sequence 4<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|
| Experimental: Treatment Sequence 5<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|
| Experimental: Treatment Sequence 6<br>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. | Drug: ALXN1840<br>* ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).<br>* Other names: Tiomolibdate choline;Drug: Placebo<br>* Placebo will be administered orally.<br>* Other names: Placebo-matching ALXN1840;Drug: Moxifloxacin<br>* Moxifloxacin (400 milligrams) will be administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | Day 1 (after dosing) through Day 70 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Thorough QT, QT Correction by Fridericia, Individual QT Correction, Wilson Disease, Electrocardiogram, Cardiac Repolarization, ALXN1840, Optimized QT Correction, QT Interval Correction