ADASUVE 2-dose Thorough QT/QTc Study

Phase 4

Completed

Conditions: Healthy Volunteers

Interventions: Drug: ADASUVE 10 mg 2 doses 2 hours apart
Drug: Inhaled Placebo
Drug: Oral moxifloxacin 400 mg
Drug: Oral placebo

Registration Number: NCT01854710

Lead Sponsor: Alexza Pharmaceuticals, Inc.

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

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 60

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Treatment sequence ABC	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ABC	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ABC	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ACB	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ACB	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ACB	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ACB	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BCA	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BCA	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BCA	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BAC	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BAC	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BAC	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CAB	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CAB	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CBA	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CAB	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CAB	Oral placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CBA	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CBA	Inhaled Placebo	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BAC	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence ABC	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence BCA	ADASUVE 10 mg 2 doses 2 hours apart	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo
Treatment sequence CBA	Oral moxifloxacin 400 mg	Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo, C = Oral moxifloxacin 400 mg + Inhaled placebo

Primary Outcome Measures

Name	Time	Method
Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	Time-matched differences in QTcI values between the maximum of the mean difference from baseline of the QTcI interval after time-matched placebo subtraction for ADASUVE treatment at 12 post-inhalation times.

Secondary Outcome Measures

Name	Time	Method
QTc Versus Loxapine Concentration	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	QTc @ Cmax based on linear and nonlinear regression of QTcI versus time matched serum loxapine concentrations
Subjects With QTcI > 450 ms	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	Numbers of Subjects with QTcI \> 450 ms at any time point
Subjects With QTcI > 480 ms	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	Numbers of Subjects with QTcI \> 480 ms (or 500 ms) at any time point
Subjects With QTcI Increase > 30 ms From Baseline	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	Numbers of Subjects with QTcI Increase \> 30 ms from Baseline at any time point
Subjects With QTcI Increase > 60 ms From Baseline	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	Numbers of Subjects with QTcI Increase \> 60 ms From Baseline at any time point