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Staccato Loxapine Thorough QT/QTc Study

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00874237
Recruitment Status : Completed
First Posted : April 2, 2009
Results First Posted : October 30, 2019
Last Update Posted : October 30, 2019
Sponsor:
Information provided by (Responsible Party):
Alexza Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Thorough QT/QTc Study
Interventions Drug: Inhaled loxapine
Drug: Inhaled placebo
Drug: Oral moxifloxacin
Drug: Oral placebo
Enrollment 48
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

Arm/Group Title Treatment Sequence ABC Treatment Sequence ACB Treatment Sequence BCA Treatment Sequence BAC Treatment Sequence CAB Treatment Sequence CBA
Hide Arm/Group Description Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg Treatment: A = Inhaled loxapine 10 mg, B = Placebo, C = Oral moxifloxacin 400 mg
Period Title: Overall Study
Started 8 8 8 8 8 8
Completed 8 7 7 8 8 8
Not Completed 0 1 1 0 0 0
Reason Not Completed
Physician Decision             0             1             0             0             0             0
Withdrawal by Subject             0             0             1             0             0             0
Arm/Group Title All Subjects Treated
Hide Arm/Group Description All 6 treatment sequences
Overall Number of Baseline Participants 48
Hide Baseline Analysis Population Description
Safety population
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 48 participants
<=18 years
0
   0.0%
Between 18 and 65 years
48
 100.0%
>=65 years
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 48 participants
40.854  (13.481)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 48 participants
Female
24
  50.0%
Male
24
  50.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 48 participants
47
1.Primary Outcome
Title Maximum Effect of ADASUVE on Cardiac Repolarization (QTc Interval Duration) at the Maximum Clinical Dose Compared to Placebo
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Inhaled Loxapine 10 mg vs Placebo Crossover Subjects
Hide Arm/Group Description:

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,

Overall Number of Participants Analyzed 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mseconds
5.418
(3.083 to 7.753)
2.Secondary Outcome
Title Cardiac Repolarization Change (QTcI) Versus Loxapine Concentration Relationship Following Treatment With Staccato Loxapine in Healthy Volunteers.
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description

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/Group Title Inhaled Loxapine 10 mg
Hide Arm/Group Description:
Largest upper 95% Upper Confidence Bound (msec) for Inhaled loxapine QTcI Differences from Placebo in Change from Predose Baseline
Overall Number of Participants Analyzed 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mseconds
4.238
(2.859 to 5.617)
3.Secondary Outcome
Title Numbers and % of Subjects With QTcI > 450 ms
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data
Arm/Group Title Inhaled Loxapine 10 mg Inhaled Placebo
Hide Arm/Group Description:
All subjects who received inhaled loxapine 10 mg (and oral) placebo and provided QTcI data
All subjects who received inhaled (and oral) placebo and provided QTcI data
Overall Number of Participants Analyzed 45 45
Measure Type: Count of Participants
Unit of Measure: Participants
1
   2.2%
1
   2.2%
4.Secondary Outcome
Title Numbers and % of Subjects With QTcI > 480 ms
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data
Arm/Group Title Inhaled Loxapine 10 mg Inhaled Placebo
Hide Arm/Group Description:
All subjects who received inhaled loxapine 10 mg (and oral) placebo and provided QTcI data
All subjects who received inhaled (and oral) placebo and provided QTcI data
Overall Number of Participants Analyzed 45 45
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
5.Secondary Outcome
Title Numbers and % of Subjects With QTcI Change > 30 ms
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data
Arm/Group Title Inhaled Loxapine 10 mg Inhaled Placebo
Hide Arm/Group Description:
All subjects who received inhaled loxapine 10 mg (and oral) placebo and provided QTcI data
All subjects who received inhaled (and oral) placebo and provided QTcI data
Overall Number of Participants Analyzed 45 45
Measure Type: Count of Participants
Unit of Measure: Participants
1
   2.2%
1
   2.2%
6.Secondary Outcome
Title Numbers and % of Subjects With QTcI Change > 60 ms
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description
QT Population (all subjects receiving placebo and inhaled loxapine and providing QT data
Arm/Group Title Inhaled Loxapine 10 mg Inhaled Placebo
Hide Arm/Group Description:
All subjects who received inhaled loxapine 10 mg (and oral) placebo and provided QTcI data
All subjects who received inhaled (and oral) placebo and provided QTcI data
Overall Number of Participants Analyzed 45 45
Measure Type: Count of Participants
Unit of Measure: Participants
0
   0.0%
0
   0.0%
7.Other Pre-specified Outcome
Title Maximum Effect of Moxifloxacin on Cardiac Repolarization (QTc Interval Duration) Compared to Placebo (Study Assay Sensitivity)
Hide Description 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
Hide Outcome Measure Data
Hide Analysis Population Description

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/Group Title Oral Moxifloxacin vs Placebo Crossover Subjects
Hide Arm/Group Description:

Largest lower 95% Upper Confidence Bound (msec) for moxifloxacin QTcI Differences from Placebo in Change from Predose Baseline

Lower CI > 5 msec at 1 or more time points establishes sensitivity of the QTc assay for the study

Overall Number of Participants Analyzed 45
Least Squares Mean (95% Confidence Interval)
Unit of Measure: mseconds
8.356
(5.825 to 10.877)
Time Frame Adverse events (AEs) were considered treatment related from the first exposure to study treatment until 30 days after the last treatment
Adverse Event Reporting Description Adverse events (AEs) were assessed predose and at 14 prespecified time points as well as whenever spontaneously reported by the subjects
 
Arm/Group Title Inhaled Loxapine 10 mg Placebo Oral Moxifloxacin
Hide Arm/Group Description

Inhaled Staccato Loxapine 10 mg single dose Oral placebo

Inhaled loxapine: Inhaled Staccato Loxapine 10 mg single dose

Oral placebo: Oral placebo

Inhaled Staccato placebo single dose Oral placebo

Inhaled placebo: Inhaled Staccato placebo single dose

Oral placebo: Oral placebo

Inhaled Staccato placebo single dose Oral moxifloxacin 400 mg

Inhaled placebo: Inhaled Staccato placebo single dose

Oral moxifloxacin: Oral Moxifloxacin 400 mg

All-Cause Mortality
Inhaled Loxapine 10 mg Placebo Oral Moxifloxacin
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/47 (0.00%)      0/47 (0.00%)      0/47 (0.00%)    
Hide Serious Adverse Events
Inhaled Loxapine 10 mg Placebo Oral Moxifloxacin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/47 (0.00%)      0/47 (0.00%)      0/47 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Inhaled Loxapine 10 mg Placebo Oral Moxifloxacin
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   38/47 (80.85%)      19/47 (40.43%)      9/47 (19.15%)    
Gastrointestinal disorders       
Dysgeusia  1  9/47 (19.15%)  9 1/47 (2.13%)  1 2/47 (4.26%)  2
Nervous system disorders       
Dizziness  1  17/47 (36.17%)  17 2/47 (4.26%)  2 4/47 (8.51%)  4
Headache  1  2/47 (4.26%)  2 4/47 (8.51%)  4 2/47 (4.26%)  2
Somnolence  1  29/47 (61.70%)  29 7/47 (14.89%)  7 2/47 (4.26%)  2
Respiratory, thoracic and mediastinal disorders       
Cough  1  7/47 (14.89%)  7 2/47 (4.26%)  2 1/47 (2.13%)  1
Skin and subcutaneous tissue disorders       
Dermatitis, contact  1  3/47 (6.38%)  3 3/47 (6.38%)  3 0/47 (0.00%)  0
1
Term from vocabulary, MedDRA (10.0)
Indicates events were collected by 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.
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Chief Scientific Officer
Organization: Alexza Pharmaceuticals, Inc
Phone: 650.944.7777
EMail: jcassella@alexza.com
Layout table for additonal information
Responsible Party: Alexza Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00874237    
Other Study ID Numbers: AMDC-004-107
February 26, 2009
First Submitted: April 1, 2009
First Posted: April 2, 2009
Results First Submitted: March 13, 2017
Results First Posted: October 30, 2019
Last Update Posted: October 30, 2019