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| ID | Type | Description | Link |
|---|---|---|---|
| February 26, 2009 |
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| Name | Class |
|---|---|
| Covance | INDUSTRY |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Treatment sequence ABC | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
|
| Treatment sequence ACB | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
|
| Treatment sequence BCA | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
|
| Treatment sequence BAC | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
|
| Treatment sequence CAB | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Inhaled loxapine | Drug | Inhaled Staccato Loxapine 10 mg single dose |
|
| Measure | Description | Time Frame |
|---|---|---|
| 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 | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
| Measure | Description | Time Frame |
|---|---|---|
| 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. |
| 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 ant any of the 9 predetermined time points | 1, 1.5, 2, 2.5, 3, 5, 8, 12, and 24 hr |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Randall R. Stoltz, MD | Covance | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Covance Clinical Research Unit Inc. | Evansville | Indiana | 47710 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 24375070 | Result | Spyker DA, Voloshko P, Heyman ER, Cassella JV. Loxapine delivered as a thermally generated aerosol does not prolong QTc in a thorough QT/QTc study in healthy subjects. J Clin Pharmacol. 2014 Jun;54(6):665-74. doi: 10.1002/jcph.257. Epub 2014 Jan 22. |
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IPD submitted to regulatory authorities. Others may contact Alexza Pharmaceuticals, Inc. Please send your request to ClinicalTrialsDoc@alexza.com
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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
132 subjects were screened.
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| ID | Title | Description |
|---|---|---|
| FG000 | Treatment Sequence ABC | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| FG001 | Treatment Sequence ACB | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| FG002 | Treatment Sequence BCA | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| FG003 | Treatment Sequence BAC | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| FG004 | Treatment Sequence CAB | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| FG005 | Treatment Sequence CBA | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
Safety population
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| ID | Title | Description |
|---|---|---|
| BG000 | All Subjects Treated | All 6 treatment sequences |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 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. | Posted | Least Squares Mean | 95% Confidence Interval | mseconds | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
|
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
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Inhaled Loxapine 10 mg | Inhaled Staccato Loxapine 10 mg single dose Oral placebo Inhaled loxapine: Inhaled Staccato Loxapine 10 mg single dose Oral placebo: Oral placebo |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Dysgeusia | Gastrointestinal disorders | MedDRA (10.0) | Systematic Assessment |
The highest approved inhaled loxapine dose of 10 mg was studied. Supratherapeutic doses were not evaluated because of tolerability concerns in healthy subjects. The inclusion of only healthy subjects is likewise a limitation of this study.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Chief Scientific Officer | Alexza Pharmaceuticals, Inc | 650.944.7777 | jcassella@alexza.com |
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| ID | Term |
|---|---|
| D008152 | Loxapine |
| D000077266 | Moxifloxacin |
| ID | Term |
|---|---|
| D003989 | Dibenzoxazepines |
| D006575 | Heterocyclic Compounds, 3-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006571 | Heterocyclic Compounds |
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Double blind, double dummy
|
| Treatment sequence CBA | Other | Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg |
|
|
| Inhaled placebo | Drug | Inhaled Staccato placebo single dose |
|
| Oral moxifloxacin | Drug | Oral moxifloxacin 400 mg |
|
| Oral placebo | Drug | Oral placebo similar in appearance to moxifloxacin 400 mg |
|
| 24 hours |
| Numbers and % of Subjects With QTcI > 450 ms | Numbers and Percents of Subjects with QTcI exceeding 450 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
| Numbers and % of Subjects With QTcI > 480 ms | Numbers and Percents of Subjects with QTcI exceeding 480 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
| Numbers and % of Subjects With QTcI Change > 30 ms | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
| Numbers and % of Subjects With QTcI Change > 60 ms | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
| Withdrawal by Subject |
|
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
|
|
| 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. | 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. | Posted | Least Squares Mean | 95% Confidence Interval | mseconds | 24 hours |
|
|
|
| Secondary | Numbers and % of Subjects With QTcI > 450 ms | Numbers and Percents of Subjects with QTcI exceeding 450 ms | QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data | Posted | Count of Participants | Participants | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
|
|
|
| Secondary | Numbers and % of Subjects With QTcI > 480 ms | Numbers and Percents of Subjects with QTcI exceeding 480 ms | QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data | Posted | Count of Participants | Participants | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
|
|
|
| Secondary | Numbers and % of Subjects With QTcI Change > 30 ms | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 30 ms | QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data | Posted | Count of Participants | Participants | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
|
|
|
| Secondary | Numbers and % of Subjects With QTcI Change > 60 ms | Numbers and Percents of Subjects with QTcI increase from baseline exceeding 60 ms | QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data | Posted | Count of Participants | Participants | 1, 2, 5, 9, 15, 30 min, 1, 3, 6, 10 and 23 hours |
|
|
|
| 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 | 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. | Posted | Least Squares Mean | 95% Confidence Interval | mseconds | 1, 1.5, 2, 2.5, 3, 5, 8, 12, and 24 hr |
|
|
|
| 0 |
| 47 |
| 0 |
| 47 |
| 38 |
| 47 |
| EG001 | Placebo | Inhaled Staccato placebo single dose Oral placebo Inhaled placebo: Inhaled Staccato placebo single dose Oral placebo: Oral placebo | 0 | 47 | 0 | 47 | 19 | 47 |
| EG002 | Oral Moxifloxacin | Inhaled Staccato placebo single dose Oral moxifloxacin 400 mg Inhaled placebo: Inhaled Staccato placebo single dose Oral moxifloxacin: Oral Moxifloxacin 400 mg | 0 | 47 | 0 | 47 | 9 | 47 |
| Dizziness | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Headache | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Somnolence | Nervous system disorders | MedDRA (10.0) | Systematic Assessment |
|
| Cough | Respiratory, thoracic and mediastinal disorders | MedDRA (10.0) | Systematic Assessment |
|
| Dermatitis, contact | Skin and subcutaneous tissue disorders | MedDRA (10.0) | Systematic Assessment |
|
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| D024841 | Fluoroquinolones |
| D042462 | 4-Quinolones |
| D015363 | Quinolones |
| D011804 | Quinolines |
| D006574 | Heterocyclic Compounds, 2-Ring |