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

Study Overview
=================
Brief Summary
-----------------
This study will investigate the effect of multiple doses of cotadutide on the cardiac activity (QTc interval) of healthy participants.

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.

Official Title
-----------------
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

Conditions
-----------------
Non-alcoholic Steatohepatitis

Intervention / Treatment
-----------------
* Drug: Cotadutide
* Drug: Cotadutide-placebo
* Drug: Moxifloxacin
* Drug: Moxifloxacin-placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
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).

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Participants will receive cotadutide and will receive a single dose of moxifloxacin-placebo on Day 1 and Day 93. | Drug: Cotadutide<br>* Participants will receive a subcutaneous injection of cotadutide.<br>Drug: Moxifloxacin-placebo<br>* Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.<br>|
| Experimental: Arm 2A<br>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: Cotadutide-placebo<br>* Participants will receive a subcutaneous injection of cotadutide-placebo.<br>Drug: Moxifloxacin<br>* Participants will receive a single oral dose of Moxifloxacin film-coated tablet.<br>Drug: Moxifloxacin-placebo<br>* Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.<br>|
| Experimental: Arm 2B<br>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: Cotadutide-placebo<br>* Participants will receive a subcutaneous injection of cotadutide-placebo.<br>Drug: Moxifloxacin<br>* Participants will receive a single oral dose of Moxifloxacin film-coated tablet.<br>Drug: Moxifloxacin-placebo<br>* Participants will receive a single oral dose of Moxifloxacin-placebo film-coated tablet.<br>|

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) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Non-alcoholic fatty liver disease, Glucagon-like peptide-1 (GLP-1) receptor