Evaluation of Possible Effects on the QTc Interval of CHF 4226 pMDI in Healthy Volunteers

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the effect of single doses of therapeutic and supratherapeutic doses of inhaled CHF 4226 pMDI on ventricular repolarization in healthy subjects compared with placebo.

Detailed Description
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The secondary purposes of this study are to 1) determine if there is a relationship between the duration of the QTc intervals and the plasma concentrations of carmoterol; 2) expand the available information on plasma pharmacokinetics and urine excretion for inhaled carmoterol at the proposed therapeutic and supra-therapeutic doses; and 3) generate additional safety information.

Official Title
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A Randomized, Double Blind, Single Dose, Positive and Placebo Controlled, Crossover Study of the Effects of Inhaled Carmoterol, at the Proposed Therapeutic and Supratherapeutic Doses, on the QTc Intervals in Healthy Subjects

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: CHF 4226 pMDI
* Drug: CHF 4226 pMDI
* Drug: Placebo
* Drug: Moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adult male or female subjects, 18-55 years of age who provided written informed consent. A body mass index (BMI) between 18 - 30, inclusive. A normal blood pressure (< 140mmHg systolic and < 90mmHg diastolic) A normal 12-lead ECG (QTcF interval < 450msec for males and < 470msec for females). A serum potassium </= 4.0mEq/L. A calculated creatinine clearance > 80mL/min. Male subjects must agree to use a medically acceptable contraceptive (abstain from sexual intercourse, or use a condom with spermicide), have had a vasectomy at least 6 months prior to study participation or have a partner who is not of childbearing potential. Exclusion Criteria: A history or presence of significant cardiovascular, pulmonary, hepatic, renal, hematologic, gastrointestinal, endocrine, immunologic, dermatologic, neurologic, or psychiatric disease. A history of sensitivity or allergy to the quinolone class of antibiotics and/or a beta 2 adrenergic receptor agonist. Clinically significant screening results (laboratory profiles, medical histories, ECGs, physical exam). Hemoglobin below the normal reference range for the testing laboratory. Abuse of alcohol or other substances. Current use of tobacco products. Subjects with a positive laboratory test result for hepatitis B, hepatitis C, HIV, controlled substances, cotinine or alcohol. Any prescription medication taken within 14 days (or 5 elimination half-lives, whichever is longer) of Study Day -2, or have taken any over-the-counter medications, including topical medications, vitamins, herbal or dietary supplements/remedies (e.g., Saint John's Wort or Milk Thistle), within 14 days of Study Day -2, or planned concomitant medication while in the study (except for acetaminophen up to 2g/day), with the exception of hormonal birth control medications or hormone replacement therapy for females. A history of additional risk factors for Torsade de Pointes (e.g., hypokalemia, history of drowning survival, family history of Long QT Syndrome, family history of Short QT Syndrome, or family history of unexplainable early sudden death). Subject is pregnant or lactating female, or female at risk of pregnancy (i.e., not using an adequate contraceptive method: surgical sterilization [e.g., bilateral tubal ligation], hormonal contraception [implantable, patch, oral], IUD, and double-barrier methods [any double combination of: male or female condom with spermicidal gel, diaphragm, sponge, cervical dap]_. Participation in a study of an investigational drug within 30 days prior to the baseline ECG. Any condition that, in the judgment of the Investigator, would place a subject at undue risk, or potentially compromise the results or interpretation of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 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
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment A<br>Single therapeutic dose of CHF 4226 pMDI | Drug: CHF 4226 pMDI<br>* Inhaled solution, single therapeutic dose<br>* Other names: Carmoterol HFA;|
| Experimental: Treatment B<br>Single supratherapeutic dose of CHF 4226 pMDI | Drug: CHF 4226 pMDI<br>* Inhaled solution, single supratherapeutic dose<br>* Other names: Carmoterol HFA;|
| Placebo Comparator: Treatment C<br>Single dose of placebo | Drug: Placebo<br>* Inhaled solution, single dose of placebo<br>|
| Active Comparator: Treatment D<br>Single dose of moxifloxacin | Drug: Moxifloxacin<br>* Tablet, oral, 400mg, single dose<br>* Other names: Avelox;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTci |  | ECGs taken every treatment period on day -1 and day +1 at -1, -0.5, -0.25, 0.08, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTcX interval (subject-specific correction of QTcF, QTcB and QTcH) |  | ECGs taken every treatment period on day -1 and day +1 at -1, -0.5, -0.25, 0.08, 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12 and 24 hrs | 
| Plasma concentration (AUC, Cmax, Tmax) |  | Each treatment period on dosing day at -0.75, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hrs | 
| Urinary excretion (Ae) |  | Each treatment period on day of dosing at -0.75, 0.58 and 24 hours. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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QTc, CHF 4226 HFA, pMDI, Carmoterol