Thorough QT/QTc Study
Conditions
Keywords
Staccato loxapine, QT/QTc, healthy volunteers, Thorough QT/QTc study, ADASUVE, inhaled loxapine
Brief summary
The purpose of the present Phase 1 study was to assess the cardiac safety of Staccato Loxapine administered to healthy volunteers in a 3 period crossover study.
Detailed description
Primary Objective: To assess the maximum effect of Staccato Loxapine on cardiac repolarization (QTc interval duration) at the anticipated maximum clinical dose compared to placebo in healthy volunteers. Secondary Objective: To assess the QTc versus loxapine concentration relationship following treatment with Staccato Loxapine in healthy volunteers.
Interventions
DRUGInhaled loxapine
Inhaled Staccato Loxapine 10 mg single dose
DRUGInhaled placebo
Inhaled Staccato placebo single dose
Oral moxifloxacin 400 mg
DRUGOral placebo
Oral placebo similar in appearance to moxifloxacin 400 mg
Sponsors
Alexza Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind, double dummy
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subjects who are in good general health and agree to use a medically acceptable and effective birth control method throughout the study.
Exclusion criteria
* Subjects who have taken prescription or nonprescription medication within 5 days of treatment, * Subjects who have had an acute illness within the last 5 days of treatment, * Subjects who are smokers, OR * Subjects who have an ECG abnormality at baseline.
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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac Repolarization Change (QTcI) Versus Loxapine Concentration Relationship Following Treatment With Staccato Loxapine in Healthy Volunteers. | 24 hours | 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. |
| Numbers and % of Subjects With QTcI > 450 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours | Numbers and Percents of Subjects with QTcI exceeding 450 ms |
| Numbers and % of Subjects With QTcI Change > 30 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms |
| Numbers and % of Subjects With QTcI Change > 60 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms |
| Numbers and % of Subjects With QTcI > 480 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours | Numbers and Percents of Subjects with QTcI exceeding 480 ms |
Other
| Measure | Time frame | Description |
|---|---|---|
| Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity) | 1, 1.5, 2, 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 ant any of the 9 predetermined time points |
Countries
United States
Participant flow
Recruitment details
132 subjects were screened.
Pre-assignment details
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
Participants by arm
| Arm | Count |
|---|---|
| All Subjects Treated All 6 treatment sequences | 48 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 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 | 48 Participants |
| Age, Continuous | 40.854 years STANDARD_DEVIATION 13.481 |
| Region of Enrollment United States | 47 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 24 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 47 | 0 / 47 | 0 / 47 |
| other Total, other adverse events | 38 / 47 | 19 / 47 | 9 / 47 |
| serious Total, serious adverse events | 0 / 47 | 0 / 47 | 0 / 47 |
Outcome results
Primary
Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
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
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo | 5.418 mseconds |
Secondary
Cardiac Repolarization Change (QTcI) Versus Loxapine Concentration Relationship Following Treatment With Staccato Loxapine in Healthy Volunteers.
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.
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Cardiac Repolarization Change (QTcI) Versus Loxapine Concentration Relationship Following Treatment With Staccato Loxapine in Healthy Volunteers. | 4.238 mseconds |
Secondary
Numbers and % of Subjects With QTcI > 450 ms
Numbers and Percents of Subjects with QTcI exceeding 450 ms
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Numbers and % of Subjects With QTcI > 450 ms | 1 Participants |
| Inhaled Placebo | Numbers and % of Subjects With QTcI > 450 ms | 1 Participants |
Secondary
Numbers and % of Subjects With QTcI > 480 ms
Numbers and Percents of Subjects with QTcI exceeding 480 ms
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Numbers and % of Subjects With QTcI > 480 ms | 0 Participants |
| Inhaled Placebo | Numbers and % of Subjects With QTcI > 480 ms | 0 Participants |
Secondary
Numbers and % of Subjects With QTcI Change > 30 ms
Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Numbers and % of Subjects With QTcI Change > 30 ms | 1 Participants |
| Inhaled Placebo | Numbers and % of Subjects With QTcI Change > 30 ms | 1 Participants |
Secondary
Numbers and % of Subjects With QTcI Change > 60 ms
Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms
Time frame: 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
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Numbers and % of Subjects With QTcI Change > 60 ms | 0 Participants |
| Inhaled Placebo | Numbers and % of Subjects With QTcI Change > 60 ms | 0 Participants |
Other Pre-specified
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 ant any of the 9 predetermined time points
Time frame: 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.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Inhaled Loxapine 10 mg vs Placebo Crossover Subjects | Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity) | 8.356 mseconds |