A Study of the Cardiac Effects of ALXN1840 in Healthy Adults

Healthy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04560816
• Other study ID #: ALXN1840-HV-107
• Status: Completed
• Phase: Phase 1
• Start date: July 24, 2020
• Est. completion date: March 24, 2021

Study information

• Verified date: September 2022
• Source: Alexion
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 57
• Est. completion date: March 24, 2021
• Est. primary completion date: March 24, 2021
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 50 Years

Eligibility

Inclusion Criteria:

1. Nonsmoker.

2. 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.

3. Willing and able to follow protocol-specified contraception requirements.

4. Participant has no clinically significant history or presence of ECG findings.

Exclusion Criteria:

1. History or presence of clinical and/or lab disorders.

2. Lymphoma, leukemia, or any malignancy within the past 5 years, or breast cancer within the past 10 years.

3. Participant has abnormal blood pressure, defined as a supine blood pressure <90/50 millimeters of mercury (mm Hg) or >140/90 mm Hg.

4. Serum potassium, calcium, or magnesium levels outside the normal range.

5. Serum copper and/or ceruloplasmin values below the lower limit of normal at Screening.

6. Female participant has hemoglobin <10.8 grams/deciliter (g/dL) and male participant has hemoglobin <12.5 g/dL.

7. Clinically significant multiple or severe allergies.

8. Alanine aminotransferase, aspartate aminotransferase, serum creatinine, or total bilirubin greater than upper limit of normal (with the exception of Gilbert's syndrome).

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• ALXN1840
ALXN1840 (120 milligrams) will be administered orally (supratherapeutic dose).
• Placebo
Placebo will be administered orally.
• Moxifloxacin
Moxifloxacin (400 milligrams) will be administered orally.

Locations

Country	Name	City	State
United States	PPD Development, LP	Austin	Texas

Sponsors (3)

Lead Sponsor	Collaborator
Alexion	ERT: Clinical Trial Technology Solutions, PPD

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Placebo-corrected Change From Baseline For QTcF (??QTcF) 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 (?QTcF). ?QTcF was based on a mixed-effects model for repeated measures (MMRM) with ?QTcF as the dependent variable; period, sequence, time, treatment, and time-by-treatment interaction as fixed effects; and baseline QTc and sex as covariates.; ??QTc = LS mean ?QTcF after ALXN1840 dosing minus LS mean ?QTcF after placebo. If the upper bound of the confidence interval (CI) of ??QTcF 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	??QTcF For Moxifloxacin Using The By-time Point Analysis	Assay sensitivity was evaluated using the by-time point analysis of the effect on ??QTc of moxifloxacin.; If ??QTcF 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
Secondary	Change From Baseline For Heart Rate (?HR)	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
Secondary	Change From Baseline QT Interval Using Fridericia's Formula (?QTcF)	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
Secondary	Change From Baseline PR Interval (?PR)	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
Secondary	Change From Baseline QRS Interval (?QRS)	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
Secondary	Placebo-corrected Change From Baseline Heart Rate (??HR)	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
Secondary	Placebo-corrected Change From Baseline PR Interval (??PR)	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
Secondary	Placebo-corrected Change From Baseline QRS Interval (??QRS)	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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