Evaluation of Possible Effects on the QTc Interval of CHF 4226 pMDI in Healthy Volunteers (CT14)

• ClinicalTrials.gov Identifier: NCT00777595
• Recruitment Status: Completed
• First Posted: October 22, 2008
• Last Update Posted: March 27, 2009
• Sponsor: Chiesi Farmaceutici S.p.A.
• Information provided by: Chiesi Farmaceutici S.p.A.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: CHF 4226 pMDI; Drug: Placebo; Drug: Moxifloxacin	Phase 1

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 47 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2008
• Actual Primary Completion Date: December 2008
• Actual Study Completion Date: December 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment A; Single therapeutic dose of CHF 4226 pMDI	Drug: CHF 4226 pMDI; Inhaled solution, single therapeutic dose; Other Name: Carmoterol HFA
Experimental: Treatment B; Single supratherapeutic dose of CHF 4226 pMDI	Drug: CHF 4226 pMDI; Inhaled solution, single supratherapeutic dose; Other Name: Carmoterol HFA
Placebo Comparator: Treatment C; Single dose of placebo	Drug: Placebo; Inhaled solution, single dose of placebo
Active Comparator: Treatment D; Single dose of moxifloxacin	Drug: Moxifloxacin; Tablet, oral, 400mg, single dose; Other Name: Avelox

Outcome Measures

Primary Outcome Measures :

1. QTci [ Time Frame: 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 :

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

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Locations

United States, North Dakota

PRACS Institute, Ltd.

Fargo, North Dakota, United States, 58104

Sponsors and Collaborators

Chiesi Farmaceutici S.p.A.

Investigators

• Principal Investigator: Robert I. Cooper, MD; PRACS Institute, Ltd.
• Study Director: Steven E. Linberg, PhD; Chiesi Farmaceutici S.p.A.

More Information

Publications:

Russell T, Riley SP, Cook JA, Lalonde RL. A perspective on the use of concentration-QT modeling in drug development. J Clin Pharmacol. 2008 Jan;48(1):9-12.

Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornøe CW, Wang Y, Zhu H, Gobburu JV. Concentration-QT relationships play a key role in the evaluation of proarrhythmic risk during regulatory review. J Clin Pharmacol. 2008 Jan;48(1):13-8. Review.

Bloomfield D, Krishna R. Commentary on the clinical relevance of concentration/QTc relationships for new drug candidates. J Clin Pharmacol. 2008 Jan;48(1):6-8.

• Responsible Party: Steven E. Linberg, Ph.D., Chiesi Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT00777595
• Other Study ID Numbers: CCD-0808-PR-0036
• First Posted: October 22, 2008
• Last Update Posted: March 27, 2009
• Last Verified: March 2009

Keywords provided by Chiesi Farmaceutici S.p.A.:

QTc; CHF 4226 HFA; pMDI; Carmoterol

Additional relevant MeSH terms:

Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Lung Diseases; Respiratory Tract Diseases; Moxifloxacin; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents