Clinical trial NCT00777595: Evaluation of Possible Effects on the QTc Interval of CHF 4226 pMDI in Healthy Volunteers
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: QTc
CHF 4226 HFA
pMDI
Carmoterol
Lead sponsor: Chiesi Farmaceutici S.p.A.
Sponsor class: INDUSTRY
First posted: 2008-10-22
Enrollment: 47
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: QTci
timeFrame: 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 outcomes:
measure: QTcX interval (subject-specific correction of QTcF, QTcB and QTcH)
timeFrame: 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
measure: Plasma concentration (AUC, Cmax, Tmax)
timeFrame: Each treatment period on dosing day at -0.75, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 hrs
measure: Urinary excretion (Ae)
timeFrame: Each treatment period on day of dosing at -0.75, 0.58 and 24 hours.
Other outcomes:
Locations:
city: Fargo
country: United States
facility: PRACS Institute, Ltd.
state: North Dakota
Study officials:
affiliation: PRACS Institute, Ltd.
name: Robert I. Cooper, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Chiesi Farmaceutici S.p.A.
name: Steven E. Linberg, PhD
role: STUDY_DIRECTOR
References:
citation: 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. doi: 10.1177/0091270007311115. No abstract available.
citation: Garnett CE, Beasley N, Bhattaram VA, Jadhav PR, Madabushi R, Stockbridge N, Tornoe 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. doi: 10.1177/0091270007307881.
citation: 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. doi: 10.1177/0091270007312257. No abstract available.