ADASUVE 2-dose Thorough QT/QTc Study

Study Overview
=================
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

Official Title
-----------------
Thorough QT/QTc Study of 2 Doses of ADASUVE® in Healthy Volunteers

Conditions
-----------------
Healthy Volunteers

Intervention / Treatment
-----------------
* Drug: ADASUVE 10 mg 2 doses 2 hours apart
* Drug: Inhaled Placebo
* Drug: Oral moxifloxacin 400 mg
* Drug: Oral placebo


Participation Criteria
=================
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.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional 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)
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Treatment sequence ABC<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|
| Other: Treatment sequence ACB<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|
| Other: Treatment sequence BCA<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|
| Other: Treatment sequence BAC<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|
| Other: Treatment sequence CAB<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|
| Other: Treatment sequence CBA<br>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 | Drug: ADASUVE 10 mg 2 doses 2 hours apart<br>* Inhaled loxapine 10 mg 2 doses 2 hours apart<br>* Other names: Staccato Loxapine;Drug: Inhaled Placebo<br>* Staccato placebo via inhalation x 2 at 2 hours apart<br>Drug: Oral moxifloxacin 400 mg<br>* Oral moxifloxacin 400 mg single dose<br>* Other names: AVELOX;Drug: Oral placebo<br>* Oral capsule identical in appearance to moxifloxacin<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo | 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. | 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 Outcome Measures

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

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
ADASUVE, inhaled loxapine, thorough QT/QTc study