A Study to Evaluate the Effect of Carbetocin on the QT/QTc Interval in Healthy Subjects

Study Overview
=================
Brief Summary
-----------------
Carbetocin is an oxytocin receptor agonist that selectively binds to receptors in the smooth muscle of the uterus, stimulates rhythmic contractions of the uterus, increases the frequency of existing contractions, and raises the tone of the uterine musculature. Carbetocin is approved in >100 countries for the prevention of postpartum hemorrhage due to uterine atony in women following cesarean or vaginal delivery. Per regulatory requirements, the current trial will evaluate the effects of high clinical exposure of carbetocin on the QT interval corrected for heart rate (QTc) as measured by ECG in healthy men and women.

Official Title
-----------------
A Randomized, 2-Part, Crossover Trial to Evaluate the Effect of Carbetocin on the QT/QTc Interval in Healthy Subjects

Conditions
-----------------
Postpartum Hemorrhage

Intervention / Treatment
-----------------
* Drug: Carbetocin
* Drug: Placebo
* Drug: Placebo and Moxifloxacin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy, adult, male or female subjects, 18-45 years of age, inclusive, at the screening visit. Body mass index (BMI) ≥ 18.5 and ≤29.9 kg/m2 at the screening visit. Continuous non-smoker who has not used nicotine- or tobacco-containing products for at least 3 months prior to first dosing. Exclusion Criteria: Sustained supine systolic blood pressure ≥130 mmHg or <90 mmHg, supine diastolic blood pressure ≥80 mmHg or <50 mmHg at screening or first check-in. History or presence of clinically significant ECG findings in the opinion of the Principal Investigator (PI) or designee at the screening visit or first check-in, including each of the following: HR <45 bpm or >100 bpm. QTcF is ≥450 msec (males) or ≥460 msec (females). QRS ≥110 msec; if ≥110 msec, result will be confirmed by a manual over read. PR ≥200 msec. History or presence of: Risk factors for Torsades de Pointes (e.g., heart failure, cardiomyopathy, family history of Long QT syndrome, Brugada syndrome, or sudden cardiac death). Sick sinus syndrome, second- or third-degree atrioventricular block, myocardial infarction, angina, pulmonary congestion, symptomatic or significant cardiac arrhythmia, or clinically significant conduction abnormalities. Clinically significant abnormal laboratory assessments including hypokalemia, hypercalcemia, or hypomagnesemia, in the opinion of the PI or designee.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Carbetocin<br>Single IV infusion of carbetocin | Drug: Carbetocin<br>* Single infusion of Carbetocin<br>|
| Placebo Comparator: Placebo<br>Single IV Infusion of matching placebo | Drug: Placebo<br>* Single IV infusion of matching placebo<br>|
| Active Comparator: Placebo and Moxifloxacin<br>Single IV infusion of matching placebo with a single oral dose of moxifloxacin | Drug: Placebo and Moxifloxacin<br>* Single IV infusion of matching placebo in combination with Single Oral dose of Moxifloxacin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Observed Heart rate(HR) values | Part A | Up to 240 minutes after Start of Infusion | 
| Change from baseline of HR (∆HR). | Part A | Up to 240 minutes after Start of Infusion | 
| Placebo-corrected change from baseline in QT interval (∆∆QTc) using the most appropriate HR correction method (i.e., ∆∆QTcF if Fridericia's method is used). | Part B | Up to 24 hours after Start of Infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment-emergent adverse events (TEAEs) | Part A | Up to follow-up visit (7 to 10 days after the last dose) | 
| Vital signs; Systolic blood pressure and Diastolic blood pressure | Part A. The parameters which are measured are Systolic blood pressure and Diastolic blood pressure. Each vital sign parameter value is classified as either Low, Normal or High. Summary tables will be prepared by treatment displaying the number and percentage of subjects with normal pre-administration values who had at least one markedly abnormal post-administration values. | Up to follow-up visit (7 to 10 days after the last dose) | 
| Vital signs; Pulse rate | Part A. The parameter which is measured is Pulse rate. The vital sign parameter value is classified as either Low, Normal or High. Summary tables will be prepared by treatment displaying the number and percentage of subjects with normal pre-administration values who had at least one markedly abnormal post-administration values. | Up to follow-up visit (7 to 10 days after the last dose) | 
| Vital signs; Body temperature | Part A. The parameter which is measured is Body temperature. The vital sign parameter value is classified as either Low, Normal or High. Summary tables will be prepared by treatment displaying the number and percentage of subjects with normal pre-administration values who had at least one markedly abnormal post-administration values. | Up to follow-up visit (7 to 10 days after the last dose) | 
| Vital signs; Respiratory rate | Part A. The parameter which is measured is Respiratory rate. The vital sign parameter value is classified as either Low, Normal or High. Summary tables will be prepared by treatment displaying the number and percentage of subjects with normal pre-administration values who had at least one markedly abnormal post-administration values. | Up to follow-up visit (7 to 10 days after the last dose) | 
| 12-lead safety ECGs | Part A. The parameters which are measured are QT, QTc, QTcF, QRS, PR, RR and HR. Subjects' maximum change from baseline and subject's maximum post-baseline values in ECG parameters will be categorized and the number and percentage of subjects in each group will be summarized. The results will be interpreted as normal, abnormal, not clinically significant or abnormal clinically significant, and the interpretation will be summarized for each treatment and scheduled time point using frequency counts and percentages. | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Blood Urea Nitrogen | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Bilirubin Total | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Bilirubin direct | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Alkaline phosphatase | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Aspartate aminotransferase | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Alanine aminotransferase | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Albumin | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Sodium | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Potassium | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Magnesium | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Chloride | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Fasting glucose | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Clinical chemistry: Changes in Concentration of Creatinine | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Hematology: Changes in Concentration of Hemoglobin | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Hematology: Changes in Concentration of Hematocrit | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Hematology: Changes in Concentration of Total and differential leukocyte count | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Hematology: Changes in Concentration of Red blood cell count | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Hematology: Changes in Concentration of Platelet count | Part A. Assessed by blood sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of pH | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of specific gravity | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Protein | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Glucose | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Bilirubin | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Blood | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Nitrite | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Urobilinogen | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| Urinalysis parameters: Concentration of Leukocyte esterase | Part A. Assessed by urine sample collection | Up to follow-up visit (7 to 10 days after the last dose) | 
| ∆HR, PR change from baseline (∆PR), RR change from baseline (∆RR), QRS change from baseline (∆QRS), and QTcF change from baseline (∆QTcF), if not selected as the primary endpoint. | Part B | Up to 24 hours after Start of Infusion | 
| Placebo-corrected ∆HR (∆∆HR), placebo-corrected ∆PR (∆∆PR), placebo-corrected ∆RR (∆∆RR), placebo-corrected ∆QRS (∆∆QRS), and ∆∆QTcF, if not selected as the primary endpoint | Part B | Up to 24 hours after Start of Infusion | 
| Categorical outliers for QTcF | Part B | Up to 24 hours after Start of Infusion | 
| Categorical outliers for HR | Part B | Up to 24 hours after Start of Infusion | 
| Categorical outliers for PR | Part B | Up to 24 hours after Start of Infusion | 
| Categorical outliers for QRS | Part B | Up to 24 hours after Start of Infusion | 
| Abnormalities in T wave morphology and pathologic U waves, as appropriate. | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: AUClast | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: AUCinf | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: AUC%extrap | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: Cmax | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: Tmax | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: t½ | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: MRTinf | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: CL | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: Vss | Part B | Up to 24 hours after Start of Infusion | 
| Carbetocin PK parameters: Vz. | Part B | Up to 24 hours after Start of Infusion | 
| ∆∆QTc (i.e., ∆∆QTcF or the most appropriate HR correction method) following administration of moxifloxacin. | Part B | Up to 24 hours after Start of Infusion | 
| TEAEs | Part B | End of Trial (Up to 25 days) | 
| Vital signs; Systolic blood pressure and Diastolic blood pressure | Part B. The parameters which are measured are Systolic blood pressure and Diastolic blood pressure. Each vital sign parameter value is classified as either Low, Normal or High | End of Trial (Up to 25 days) | 
| Vital signs; Pulse rate | Part B. The parameter which is measured is Pulse rate. The sign parameter value is classified as either Low, Normal or High | End of Trial (Up to 25 days) | 
| Vital signs; Body temperature | Part B. The parameter which is measured is Body temperature. The sign parameter value is classified as either Low, Normal or High | End of Trial (Up to 25 days) | 
| Vital signs; Respiratory rate | Part B. The parameter which is measured is Respiratory rate. The sign parameter value is classified as either Low, Normal or High | End of Trial (Up to 25 days) | 
| 12-lead safety ECGs | Part B. The parameters which are measured are QT, QTc, QTcF, QRS, PR, RR and HR. The results will be interpreted as normal, abnormal, not clinically significant or abnormal clinically significant. | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Blood Urea Nitrogen | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Bilirubin total | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Bilirubin direct | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Alkaline phosphatase | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Aspartate aminotransferase | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Alanine aminotransferase | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Albumin | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Sodium | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Potassium | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Magnesium | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Chloride | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Fasting glucose | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Clinical chemistry: Changes in Concentration of Creatinine | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Hematology: Changes in Concentration of Hemoglobin | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Hematology: Changes in Concentration of Hematocrit | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Hematology: Changes in Concentration of Total and Differential leukocyte count | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Hematology: Changes in Concentration of Red blood cell count | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Hematology: Changes in Concentration of Platelet count | Part B. Assessed by blood sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of pH | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Specific gravity | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Protein | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Glucose | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Bilirubin | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Blood | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Nitrite | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Urobilinogen | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) | 
| Urinalysis parameters: Concentration of Leukocyte esterase | Part B. Assessed by urine sample collection | End of Trial (Up to 25 days) |