Trial Outcomes & Findings for Staccato Loxapine Thorough QT/QTc Study (NCT NCT00874237)

NCT ID: NCT00874237

Last Updated: 2019-10-30

Results Overview

Largest of the upper CIs of the 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 prespecified post inhalation times

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 48 participants
• Primary outcome timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours
• Results posted on: 2019-10-30

Participant Flow

132 subjects were screened.

Of the 132 subjects who were screened for the study, 69 did not meet criteria, 5 withdrew consent, 1 no show, 9 enrollment full. 48 (36.4%) were randomized and received at least 1 dose of study medication, and 46 completed the study

Participant milestones

Measure	Treatment Sequence ABC Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence ACB Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence BCA Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence BAC Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence CAB Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence CBA Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg
Overall Study STARTED	8	8	8	8	8	8
Overall Study COMPLETED	8	7	7	8	8	8
Overall Study NOT COMPLETED	0	1	1	0	0	0

Reasons for withdrawal

Measure	Treatment Sequence ABC Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence ACB Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence BCA Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence BAC Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence CAB Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg	Treatment Sequence CBA Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg
Overall Study Physician Decision	0	1	0	0	0	0
Overall Study Withdrawal by Subject	0	0	1	0	0	0

Baseline Characteristics

Staccato Loxapine Thorough QT/QTc Study

Baseline characteristics by cohort

Measure	All Subjects Treated n=48 Participants All 6 treatment sequences
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	48 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants
Age, Continuous	40.854 years STANDARD_DEVIATION 13.481 • n=5 Participants
Sex: Female, Male Female	24 Participants n=5 Participants
Sex: Female, Male Male	24 Participants n=5 Participants
Region of Enrollment United States	47 participants n=5 Participants

PRIMARY outcome

Timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours

Population: QT population (all patients receiving both placebo and 10 mg inhaled loxapine. 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.

Largest of the upper CIs of the 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 prespecified post inhalation times

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo All subjects who received inhaled (and oral) placebo and provided QTcI data
Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo	5.418 mseconds Interval 3.083 to 7.753	—

SECONDARY outcome

Timeframe: 24 hours

Population: QT + PK Population (all subjects receiving placebo and loxapine who provided QTc and pharmacokinetic data). LSM and CI statistics were based on the individual (within subject) corrected differences between loxapine and placebo exposures per ICH Guideline E14 for a thorough QT study.

QTcI change at the median loxapine concentration (32.2 mcg/mL) based on nonlinear regression of QTcI versus log of time matched serum loxapine concentrations. This analysis looks for repolarization versus concentration relationship in a positive or negative thorough QT/QTc study result.

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo All subjects who received inhaled (and oral) placebo and provided QTcI data
Cardiac Repolarization Change (QTcI) Versus Loxapine Concentration Relationship Following Treatment With Staccato Loxapine in Healthy Volunteers.	4.238 mseconds Interval 2.859 to 5.617	—

SECONDARY outcome

Timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours

Population: QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data

Numbers and Percents of Subjects with QTcI exceeding 450 ms

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo n=45 Participants All subjects who received inhaled (and oral) placebo and provided QTcI data
Numbers and % of Subjects With QTcI > 450 ms	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours

Population: QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data

Numbers and Percents of Subjects with QTcI exceeding 480 ms

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo n=45 Participants All subjects who received inhaled (and oral) placebo and provided QTcI data
Numbers and % of Subjects With QTcI > 480 ms	0 Participants	0 Participants

SECONDARY outcome

Timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours

Population: QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data

Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo n=45 Participants All subjects who received inhaled (and oral) placebo and provided QTcI data
Numbers and % of Subjects With QTcI Change > 30 ms	1 Participants	1 Participants

SECONDARY outcome

Timeframe: 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours

Population: QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data

Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo n=45 Participants All subjects who received inhaled (and oral) placebo and provided QTcI data
Numbers and % of Subjects With QTcI Change > 60 ms	0 Participants	0 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 1, 1.5, 2, 2.5, 3, 5, 8, 12, and 24 hr

Population: All subjects who completed both Inhaled placebo + oral placebo and moxifloxacin 400 mg + Inhaled placebo. 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 ant any of the 9 predetermined time points

Outcome measures

Measure	Inhaled Loxapine 10 mg vs Placebo Crossover Subjects n=45 Participants Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline All upper CIs \< 10 msec establishes this as a negative Thorough QT/QTc Study as defined in the ICH E14 guideline, 2005,	Inhaled Placebo All subjects who received inhaled (and oral) placebo and provided QTcI data
Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)	8.356 mseconds Interval 5.825 to 10.877	—

Adverse Events

Inhaled Loxapine 10 mg

Serious events: 0 serious events

Other events: 38 other events

Deaths: 0 deaths

Placebo

Serious events: 0 serious events

Other events: 19 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

Measure	Inhaled Loxapine 10 mg n=47 participants at risk Inhaled Staccato Loxapine 10 mg single dose Oral placebo Inhaled loxapine: Inhaled Staccato Loxapine 10 mg single dose Oral placebo: Oral placebo	Placebo n=47 participants at risk Inhaled Staccato placebo single dose Oral placebo Inhaled placebo: Inhaled Staccato placebo single dose Oral placebo: Oral placebo	Oral Moxifloxacin n=47 participants at risk Inhaled Staccato placebo single dose Oral moxifloxacin 400 mg Inhaled placebo: Inhaled Staccato placebo single dose Oral moxifloxacin: Oral Moxifloxacin 400 mg
Gastrointestinal disorders Dysgeusia	19.1% 9/47 • Number of events 9 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	2.1% 1/47 • Number of events 1 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
Nervous system disorders Dizziness	36.2% 17/47 • Number of events 17 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	8.5% 4/47 • Number of events 4 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
Nervous system disorders Headache	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	8.5% 4/47 • Number of events 4 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
Nervous system disorders Somnolence	61.7% 29/47 • Number of events 29 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	14.9% 7/47 • Number of events 7 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
Respiratory, thoracic and mediastinal disorders Cough	14.9% 7/47 • Number of events 7 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	4.3% 2/47 • Number of events 2 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	2.1% 1/47 • Number of events 1 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
Skin and subcutaneous tissue disorders Dermatitis, contact	6.4% 3/47 • Number of events 3 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	6.4% 3/47 • Number of events 3 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects	0.00% 0/47 • Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects

Additional Information

Chief Scientific Officer

Alexza Pharmaceuticals, Inc

Phone: 650.944.7777

Email: jcassella@alexza.com

Results disclosure agreements

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

Restriction type: LTE60