ADASUVE 2-dose Thorough QT/QTc Study

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

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.

Study Overview

• Status: Completed
• 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

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

• Study Type: Interventional
• Enrollment (Actual): 60
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Zuidlaren, Netherlands
    • PRA International

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

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

Number of Arms

6

Arms and Interventions

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

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)	A thorough QT/QTc study may be considered to have demonstrated assay sensitivity if 1 or more of the lower 95% CI values exceeds 5 msec	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr

Collaborators and Investigators

• Sponsor: Alexza Pharmaceuticals, Inc.
• Investigators: Principal Investigator: Teresa Nunes, MD, PRA Health Sciences

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: May 1, 2013
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: May 8, 2013
• First Submitted That Met QC Criteria: May 13, 2013
• First Posted (Estimate): May 15, 2013

Study Record Updates

• Last Update Posted (Actual): October 18, 2017
• Last Update Submitted That Met QC Criteria: September 26, 2017
• Last Verified: July 1, 2013

More Information

Terms related to this study

• Keywords: inhaled loxapine; ADASUVE; thorough QT/QTc study
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Dopamine Agents; Dopamine Antagonists; Moxifloxacin; Loxapine
• Other Study ID Numbers: AMDC-204-407; 204-407 (Other Identifier: Alexza Pharmaceuticals, Inc)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: IPD submitted to regulatory authorities. Others may contact Alexza Pharmaceuticals, Inc. Please send your request to ClinicalTrialsInfo@alexza.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes