A Thorough QTC Study to Assess the Effect of Cotadutide on Cardiac Repolarization in Healthy Participants

A Thorough QTc Evaluation of the Effect of Cotadutide on Cardiac Repolarization in Healthy Participants: A Randomized, Double-blind, Placebo-controlled, 3-arm Parallel Study With a Nested Crossover Design for Positive Control With Moxifloxacin Administration

This study will investigate the effect of multiple doses of cotadutide on the cardiac activity (QTc interval) of healthy participants.

Study Overview

• Status: Terminated
• Conditions: Non-alcoholic Steatohepatitis
• Intervention / Treatment: Drug: Cotadutide; Drug: Moxifloxacin-placebo; Drug: Cotadutide-placebo; Drug: Moxifloxacin

Detailed Description

This study will be a randomized, double-blind, placebo-controlled 3-arm parallel study with a nested crossover design for positive control with moxifloxacin administration in healthy male and female participants.

Participants will be randomized to receive treatment with either cotadutide during the 13-week treatment period (Arm 1) or cotadutide-placebo (Arm 2).

The cotadutide-placebo treatment arm will be further divided into 2 subgroups (Arms 2A and 2B), in a nested crossover design for only the placebo-treated participants.

Participants will be randomized in a 2:1:1 ratio to Arm 1, Arm 2A, and Arm 2B.

Approximately 80 participants will be randomized to have 64 evaluable participants in the study.

Each participant will be involved in the study for approximately 22 weeks.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Berlin, Germany, 14050
    • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and female participants of age 18 to 55 years.
• Females must have a negative pregnancy test.
• Have a Body Mass Index (BMI) of ≥ 18 and ≤ 29.9 kg/m^2.

Exclusion Criteria:

• History or presence of any clinically significant disease or disorder.
• History or presence of gastrointestinal, hepatic or renal disease, or any other condition (including gastrointestinal surgery) known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• History of acute or chronic pancreatitis.
• Family history of sudden cardiac death before the age of 50 of a first-degree relative.
• History of additional risk factors for Torsade de Pointes (eg, heart failure, clinically important bradycardia and electrolyte disturbances eg, hypokalemia, hypocalcemia, hypomagnesemia or family history of long QT syndrome).
• History of neoplastic disease
• Any clinically significant abnormalities in clinical chemistry, hematology, urinalysis results or vital signs.
• Any clinically significant abnormalities in rhythm, conduction, or morphology of the 12-lead resting electrocardiogram (ECG).
• Any positive result on screening for serum hepatitis B surface antigen OR anti-HBc antibody, indicative of active hepatitis B (ie, participants with positive anti-HBc antibody result are acceptable if anti HBc IgM antibodies are negative), hepatitis C antibody, and Human immunodeficiency virus (HIV) antibody.
• Current smokers or those who have smoked or used nicotine products (including e-cigarettes).
• Known or suspected history of alcohol or drug abuse or excessive intake of alcohol.
• Use of drugs with enzyme-inducing properties such as St John's Wort.
• Participant has a positive test result for SARS-CoV-2 RT-PCR during screening period or at baseline.
• Participant has clinical signs and symptoms consistent with COVID-19 or a history of severe COVID-19 (hospitalization, extracorporeal membrane oxygenation, mechanically ventilated).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Participants will receive cotadutide and will receive a single dose of moxifloxacin-placebo on Day 1 and Day 93.	Drug: Cotadutide; Participants will receive a subcutaneous injection of cotadutide.; Drug: Moxifloxacin-placebo; Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.
Experimental: Arm 2A; Participants will receive a single dose of moxifloxacin (Day 1) prior to initiating treatment with cotadutide-placebo for up to 13 weeks, followed by a single dose of moxifloxacin-placebo on Day 93.	Drug: Moxifloxacin-placebo; Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.; Drug: Cotadutide-placebo; Participants will receive a subcutaneous injection of cotadutide-placebo.; Drug: Moxifloxacin; Participants will receive a single oral dose of Moxifloxacin film-coated tablet.
Experimental: Arm 2B; Participants will receive a single dose of moxifloxacin-placebo (Day 1) prior to initiating treatment with cotadutide-placebo for up to 13 weeks, followed by a single dose of moxifloxacin on Day 93.	Drug: Moxifloxacin-placebo; Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.; Drug: Cotadutide-placebo; Participants will receive a subcutaneous injection of cotadutide-placebo.; Drug: Moxifloxacin; Participants will receive a single oral dose of Moxifloxacin film-coated tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-matched change-from-baseline Fridericia's correction of QT interval (QTcF)	Time-matched change-from-baseline QTcF after cotadutide administration compared with placebo will be assesed using a C-QTc interval analysis. The method that removes the HR dependence of the QT interval most efficiently will be chosen as the primary correction method and its corresponding change from baseline QTc will be the primary endpoint.	Up to Day 92

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in QTcF	Change from baseline in QTcF after moxifloxacin administration compared with placebo will be assessed.	Up to Day 94
Change from baseline in Heart rate (HR)	The effect of cotadutide on HR will be assessed.	From Day 2 up to Day 92 or early discontinuation
Change from baseline in PR interval	The effect of cotadutide on PR interval will be assessed.	From Day 2 up to Day 92 or early discontinuation
Change from baseline in QRS interval	The effect of cotadutide on QRS will be assessed.	From Day 2 up to Day 92 or early discontinuation
Number of participants with significant change in QTcF	The presence of categorical outliers for QTc after cotadutide administration will be assessed.	From Day 2 up to Day 92 or early discontinuation
Number of participants with significant change in HR	The presence of categorical outliers for HR after cotadutide administration will be assessed.	From Day 2 up to Day 92 or early discontinuation
Number of participants with significant change in PR interval	The presence of categorical outliers for PR after cotadutide administration will be assessed.	From Day 2 up to Day 92 or early discontinuation
Number of participants with significant change in QRS interval	The presence of categorical outliers for QRS after cotadutide administration will be assessed.	From Day 2 up to Day 92 or early discontinuation
Number of treatment-emergent changes in T-wave morphology	Morphological changes in the T-U complex after cotadutide administration will be investigated.	From Day 2 up to Day 92 or early discontinuation
Number of treatment-emergent changes in U-waves presence	Morphological changes in the T-U complex after cotadutide administration will be investigated.	From Day 2 up to Day 92 or early discontinuation
Area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUClast) of cotadutide	AUClast as a variable of the pharmacokinetics (PK) of cotadutide will be assessed.	Day 57 and Day 91
Area under concentration-time curve in the dose interval (AUCtau) of cotadutide	AUCtau as a variable of the PK of cotadutide will be assessed.	Day 57 and Day 91
Maximum observed plasma concentration (Cmax) of cotadutide	Cmax as a variable of the PK of cotadutide will be assessed.	Day 57 and Day 91
Time to reach maximum observed plasma concentration (tmax) of cotadutide	tmax as a variable of the PK of cotadutide will be assessed.	Day 57 and Day 91
Change from baseline in mean systolic blood pressure (SBP)	The effect of cotadutide on blood pressure (BP) by Ambulatory blood pressure monitoring (ABPM) will be investigated.	Up to Day 92
Change from baseline in mean diastolic blood pressure (DBP)	The effect of cotadutide on BP by ABPM will be investigated.	Up to Day 92
Change from baseline in mean HR	The effect of cotadutide on HR by ABPM will be investigated.	Up to Day 92
Placebo-corrected mean change from baseline in SBP	The effect of cotadutide on BP by ABPM will be investigated.	Up to Day 92
Placebo-corrected mean change from baseline in DBP	The effect of cotadutide on BP by ABPM will be investigated.	Up to Day 92
Placebo-corrected mean change from baseline in HR	The effect of cotadutide on HR by ABPM will be investigated.	Up to Day 92
Number of participants with significant change in SBP	The effect of cotadutide on BP by ABPM will be investigated.	Up to Day 92
Number of participants with change in DBP	The effect of cotadutide on BP by ABPM will be investigated.	Up to Day 92
Number of participants with significant change in HR	The effect of cotadutide on HR by ABPM will be investigated.	Up to Day 92
Number of participants with Adverse Events (AEs)	The safety and tolerability of cotadutide will be assessed.	Up to follow-up visit 28 days post last dose (approximately Day 120)
Number of participants with Antidrug Antibodies to cotadutide	The immunogenicity of cotadutide will be evaluated.	Day 2, 30, 57, 91 and Day 120 (follow-up visit 28 days post last dose)

Collaborators and Investigators

• Sponsor: AstraZeneca

Study record dates

Study Major Dates

• Study Start (Actual): January 3, 2023
• Primary Completion (Actual): March 10, 2023
• Study Completion (Actual): March 10, 2023

Study Registration Dates

• First Submitted: December 20, 2022
• First Submitted That Met QC Criteria: December 20, 2022
• First Posted (Actual): December 30, 2022

Study Record Updates

• Last Update Posted (Actual): April 5, 2023
• Last Update Submitted That Met QC Criteria: April 1, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Non-alcoholic fatty liver disease; Glucagon-like peptide-1 (GLP-1) receptor
• Additional Relevant MeSH Terms: Digestive System Diseases; Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination
• Other Study ID Numbers: D5671C00010; 2022-002479-12 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Qualified researchers can request access to anonymized individual patient-level data from AstraZeneca group of companies sponsored clinical trials via the request portal. All requests will be evaluated as per the AZ disclosure commitment: https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Yes, indicates that AZ are accepting requests for IPD, but this does not mean all requests will be shared.

• IPD Sharing Time Frame: AstraZeneca will meet or exceed data availability as per the commitments made to the EFPIA Pharma Data Sharing Principles. For details of our timelines, please refer to our disclosure commitment at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.
• IPD Sharing Access Criteria: When a request has been approved AstraZeneca will provide access to the de-identified individual patient-level data in an approved sponsored tool. Signed Data Sharing Agreement (non-negotiable contract for data accessors) must be in place before accessing requested information. Additionally, all users will need to accept the terms and conditions of the SAS MSE to gain access. For additional details, please review the Disclosure Statements at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No