Clinical trial NCT01854710: ADASUVE 2-dose Thorough QT/QTc Study
Official title: Thorough QT/QTc Study of 2 Doses of ADASUVE® in Healthy Volunteers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Healthy Volunteers
Keywords: ADASUVE
inhaled loxapine
thorough QT/QTc study
Lead sponsor: Alexza Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2013-05-15
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Single-center, randomized, double-blind, double-dummy, 2-dose, 3-period, active- and placebo-controlled, crossover QT/QTc and pharmacokinetic (PK) study of ADASUVE in healthy volunteers. All dosing and treatment-day follow-up in the study was conducted in the clinical research unit (CRU)
Primary purpose: OTHER

Brief summary: Assess the potential effects on the QT interval of 2 consecutive doses of ADASUVE administered 2 hours apart, in relation to placebo and an active control in healthy volunteers.

Detailed description: It has been shown in a pre-marketing clinical study that clinically relevant QT prolongation does not appear to be associated with a single dose of ADASUVE. The potential risk of QTc prolongation following repeat dosing is unknown. Therefore the current study will assess the potential effects on the QT interval of 2 consecutive doses of ADASUVE administered 2 hours apart, in relation to placebo and an active control in healthy volunteers.

The study hypothesis H0: Placebo-subtracted max mean dQTc \> 10 msec

Eligibility criteria: Inclusion Criteria:

* Male and female subjects between the ages of 18 to 65 years, inclusive.
* Body mass index (BMI) ≥18 and ≤32.
* Subjects who are willing and able to comply with the study schedule and requirements, and stay at the CRU for a 4-day period and 2 consecutive 3-day periods.
* Subjects who speak, read, and understand English and/or Dutch and are willing and able to provide written informed consent on an IEC approved form prior to the initiation of any study procedures.
* Subjects who are in good general health prior to study participation
* Female or male participants who agree to use a medically acceptable and effective birth control method

Exclusion Criteria:

* Subjects who regularly consume large amounts of xanthine-containing substances (≥ 5 cups of coffee/day).
* Subjects who have taken prescription or nonprescription medication within 5 days of Visit 2.
* Subjects who have had an acute illness within the last 5 days of Visit 2.
* Subjects who have smoked tobacco within the last 30 days or who have a positive cotinine test.
* Subjects who have a history of HIV, anti-HCV or HbsAg positivity.
* Subjects who have a history within the past 2 years of drug or alcohol dependence or abuse as defined by DSM-IV.
* Subjects who test positive for alcohol or have a positive urine drug screen.
* Subjects who have a history of allergy or intolerance to loxapine or amoxapine or history of bronchospasm following inhaled loxapine treatment.
* Subjects who have an ECG abnormality.
* Subjects who have hypotension, or hypertension.
* Subjects who have a history of unstable angina, syncope, coronary artery disease, myocardial infarction, congestive heart failure, transient ischemic attack, history of convulsions or other neurological disorder.
* Subjects who have a current history of asthma, chronic obstructive lung disease, or any other lung disease associated with bronchospasm.
* Subjects who use medications to treat airways disease, such as asthma or COPD.
* Subjects who have any acute respiratory signs/symptoms (e.g., wheezing).
* Female subjects who have a positive pregnancy test at screening or at admission to any of the treatment visits, or are breastfeeding.
* Subjects who have received an investigational drug within 60 days prior to the Screening Visit.

Primary outcomes:
measure: Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
Secondary outcomes:
measure: QTc Versus Loxapine Concentration
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
measure: Subjects With QTcI > 450 ms
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
measure: Subjects With QTcI > 480 ms
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
measure: Subjects With QTcI Increase > 30 ms From Baseline
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
measure: Subjects With QTcI Increase > 60 ms From Baseline
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
Other outcomes:
measure: Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)
timeFrame: Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr
Locations:
city: Zuidlaren
country: Netherlands
facility: PRA International
Study officials:
affiliation: PRA Health Sciences
name: Teresa Nunes, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther. 2015 Nov;53(11):963-71. doi: 10.5414/CP202457.
citation: Cassella JV, Spyker DA, Yeung PP. A randomized, placebo-controlled repeat-dose thorough QT study of inhaled loxapine in healthy volunteers. Int J Clin Pharmacol Ther. 2015 Oct 7. doi: 10.5414/CP202457. Online ahead of print.