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Trial Outcomes & Findings for ADASUVE 2-dose Thorough QT/QTc Study (NCT NCT01854710)

NCT ID: NCT01854710

Last Updated: 2017-10-18

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

60 participants

Primary outcome 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

Results posted on

2017-10-18

Participant Flow

Participant milestones

Participant milestones
Measure
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
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
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
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
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
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
Overall Study
STARTED
10
10
10
10
10
10
Overall Study
COMPLETED
6
7
8
8
8
8
Overall Study
NOT COMPLETED
4
3
2
2
2
2

Reasons for withdrawal

Reasons for withdrawal
Measure
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
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
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
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
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
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
Overall Study
Withdrawal by Subject
2
1
0
0
0
0
Overall Study
CRI procedural error
2
2
2
2
2
2

Baseline Characteristics

ADASUVE 2-dose Thorough QT/QTc Study

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
All Subjects Treated
n=60 Participants
All 6 treatment sequences = Safety Population
Age, Categorical
<=18 years
0 Participants
n=99 Participants
Age, Categorical
Between 18 and 65 years
60 Participants
n=99 Participants
Age, Categorical
>=65 years
0 Participants
n=99 Participants
Age, Continuous
33.8 years
STANDARD_DEVIATION 14.89 • n=99 Participants
Sex: Female, Male
Female
29 Participants
n=99 Participants
Sex: Female, Male
Male
31 Participants
n=99 Participants
Region of Enrollment
Netherlands
60 participants
n=99 Participants

PRIMARY outcome

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

Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between Adasuve and placebo exposures per ICH Guideline E14 for a thorough QT study.

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.

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
4.04 msec
Interval 1.77 to 6.31
—

SECONDARY outcome

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

Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between Adasuve and placebo exposures per ICH Guideline E14 for a thorough QT study.

QTc @ Cmax based on linear and nonlinear regression of QTcI versus time matched serum loxapine concentrations

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
QTc Versus Loxapine Concentration
2.6 msec
Interval 1.2 to 4.1
—

SECONDARY outcome

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

Population: QT population -- Comparisons were based on corrected differences between Adasuve and placebo (excluding moxifloxacin) exposure per ICH Guideline E14 for a thorough QT study.

Numbers of Subjects with QTcI \> 450 ms at any time point

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
n=44 Participants
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Subjects With QTcI > 450 ms
2 Participants
2 Participants

SECONDARY outcome

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

Population: QT population -- Comparisons were based on corrected differences between Adasuve and placebo (excluding moxifloxacin) exposure per ICH Guideline E14 for a thorough QT study.

Numbers of Subjects with QTcI \> 480 ms (or 500 ms) at any time point

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
n=44 Participants
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Subjects With QTcI > 480 ms
0 Participants
0 Participants

SECONDARY outcome

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

Population: QT population -- Comparisons were based on corrected differences between Adasuve and placebo (excluding moxifloxacin) exposure per ICH Guideline E14 for a thorough QT study.

Numbers of Subjects with QTcI Increase \> 30 ms from Baseline at any time point

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
n=44 Participants
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Subjects With QTcI Increase > 30 ms From Baseline
0 Participants
1 Participants

SECONDARY outcome

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

Population: QT population -- Comparisons were based on corrected differences between Adasuve and placebo (excluding moxifloxacin) exposure per ICH Guideline E14 for a thorough QT study.

Numbers of Subjects with QTcI Increase \> 60 ms From Baseline at any time point

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
n=44 Participants
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Subjects With QTcI Increase > 60 ms From Baseline
0 Participants
0 Participants

OTHER_PRE_SPECIFIED outcome

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

Population: QT population -- LSM and CI statistics were based on the individual (within subject) corrected differences between moxifloxacin and placebo exposures per ICH Guideline E14 for a thorough QT study.

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

Outcome measures

Outcome measures
Measure
ADASUVE-Placebo Crossover Subjects
n=44 Participants
All subjects who completed both treatments A and B: Treatment: A = Inhaled loxapine (2 doses of 10 mg 2 hours apart) + oral placebo, B = Inhaled placebo + oral placebo. The analyses are based on a within (paired) comparison of the time matched drug - placebo QTc values.
ADASUVE 10 mg x 2 Doses
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)
10.47 msec
Interval 8.13 to 12.81
—

Adverse Events

Inhaled Placebo + Oral Placebo

Serious events: 0 serious events
Other events: 15 other events
Deaths: 0 deaths

ADASUVE 10 mg x 2 Doses

Serious events: 0 serious events
Other events: 38 other events
Deaths: 0 deaths

Oral Moxifloxacin

Serious events: 0 serious events
Other events: 9 other events
Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure
Inhaled Placebo + Oral Placebo
n=49 participants at risk
Staccato Placebo 2 doses 2 hours apart + Oral Placebo Staccato Placebo 2 doses 2 hours apart: Inhaler with no drug in it to mimic the ADASUVE inhaler Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
ADASUVE 10 mg x 2 Doses
n=52 participants at risk
ADASUVE 10 mg 2 doses 2 hours apart + Oral Placebo ADASUVE 10 mg 2 doses 2 hours apart: inhaled loxapine Placebo (for moxifloxacin): placebo capsule to mimic moxifloxacin 400 mg
Oral Moxifloxacin
n=49 participants at risk
Staccato Placebo 2 doses 2 hours apart + Oral moxifloxacin 400 mg Oral moxifloxacin 400 mg Staccato Placebo 2 doses 2 hours apart: Inhaler with no drug in it to mimic the ADASUVE inhaler
Gastrointestinal disorders
Dry mouth
0.00%
0/49 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
7.7%
4/52 • Number of events 4 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
0.00%
0/49 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
Gastrointestinal disorders
Dysgeusia
6.1%
3/49 • Number of events 3 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
15.4%
8/52 • Number of events 8 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
4.1%
2/49 • Number of events 2 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
General disorders
Fatigue
4.1%
2/49 • Number of events 2 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
25.0%
13/52 • Number of events 13 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
4.1%
2/49 • Number of events 2 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
Nervous system disorders
Dizziness
8.2%
4/49 • Number of events 4 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
23.1%
12/52 • Number of events 12 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
0.00%
0/49 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
Nervous system disorders
Headache
10.2%
5/49 • Number of events 5 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
5.8%
3/52 • Number of events 3 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
4.1%
2/49 • Number of events 2 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
Nervous system disorders
Sedation
8.2%
4/49 • Number of events 4 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
26.9%
14/52 • Number of events 14 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
4.1%
2/49 • Number of events 2 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
Nervous system disorders
Somnolence
2.0%
1/49 • Number of events 1 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
9.6%
5/52 • Number of events 5 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points
2.0%
1/49 • Number of events 1 • From first exposure to study treatment to 30 days after last exposure to study treatment
Adverse events (AEs) were assessed pre-dose and at 12 prespecified time points

Additional Information

Chief Scientific Officer

Alexza Pharmaceuticals, Inc

Phone: 650.944.7777

Results disclosure agreements

  • Principal investigator is a sponsor employee
  • Publication restrictions are in place

Restriction type: LTE60