ADASUVE 2-dose Thorough QT/QTc Study

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

Status

Completed

Phases

Phase 4

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01854710

Enrollment

Registered

2013-05-15

Start date

2013-05-31

Completion date

2013-07-31

Last updated

2017-10-18

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Healthy Volunteers

Keywords

ADASUVE, inhaled loxapine, thorough QT/QTc study

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

Interventions

DRUGOral placebo

Oral capsule identical in appearance to moxifloxacin

DRUGADASUVE 10 mg 2 doses 2 hours apart

Inhaled loxapine 10 mg 2 doses 2 hours apart

DRUGInhaled Placebo

Staccato placebo via inhalation x 2 at 2 hours apart

DRUGOral moxifloxacin 400 mg

Oral moxifloxacin 400 mg single dose

Study design

Allocation

RANDOMIZED

Intervention model

CROSSOVER

Primary purpose

OTHER

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

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)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Yes

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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 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
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

Other

Measure	Time frame	Description
Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)	Predose, 2 min, 1, 1.5 hr, 2 hr 2 min, 2 hr 5 min, 2.5, 3, 5, 8, 12, and 24 hr	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

Countries

Netherlands

Participant flow

Participants by arm

Arm	Count
All Subjects Treated All 6 treatment sequences = Safety Population	60
Total	60

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003	FG004	FG005
Overall Study	CRI procedural error	2	2	2	2	2	2
Overall Study	Withdrawal by Subject	2	1	0	0	0	0

Baseline characteristics

Characteristic	All Subjects Treated
Age, Categorical <=18 years	0 Participants
Age, Categorical >=65 years	0 Participants
Age, Categorical Between 18 and 65 years	60 Participants
Age, Continuous	33.8 years STANDARD_DEVIATION 14.89
Region of Enrollment Netherlands	60 participants
Sex: Female, Male Female	29 Participants
Sex: Female, Male Male	31 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	0 / 49	0 / 52	0 / 49
other Total, other adverse events	15 / 49	38 / 52	9 / 49
serious Total, serious adverse events	0 / 49	0 / 52	0 / 49

Outcome results

Primary

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.