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Staccato Loxapine in Agitation (Proof of Concept)

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ClinicalTrials.gov Identifier: NCT00369577
Recruitment Status : Completed
First Posted : August 29, 2006
Results First Posted : January 2, 2018
Last Update Posted : January 2, 2018
Sponsor:
Information provided by (Responsible Party):
Alexza Pharmaceuticals, Inc.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Schizophrenia
Interventions Drug: Inhaled Placebo
Drug: Inhaled Loxapine 5 mg
Drug: Inhaled Loxapine 10 mg
Enrollment 129
Recruitment Details The study was conducted at 19 centers between Sep-2006 and Jan-2007. Patients recruited for screening were: 1) admitted to a hospital or research unit with acute agitation, 2) inpatients being treated for chronic underlying conditions who presented with acute agitation, and 3) patients with agitation treated in a psychiatric ED.
Pre-assignment Details Pre-Treatment Period was defined as the period immediately prior to dosing in which screening procedures and inclusion/exclusion criteria were used to evaluate all patients for eligibility to participate in the study.
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description Inhaled Staccato Placebo, single dose Inhaled Staccato Loxapine 5 mg, single dose Inhaled Staccato Loxapine 10 mg, single dose
Period Title: Overall Study
Started 43 45 41
Completed 43 45 40
Not Completed 0 0 1
Reason Not Completed
Withdrawal by Subject             0             0             1
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg Total
Hide Arm/Group Description Inhaled Staccato Placebo, single dose Inhaled Staccato Loxapine 5 mg, single dose Inhaled Staccato Loxapine 10 mg, single dose Total of all reporting groups
Overall Number of Baseline Participants 43 45 41 129
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 45 participants 41 participants 129 participants
<=18 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Between 18 and 65 years
43
 100.0%
45
 100.0%
41
 100.0%
129
 100.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 43 participants 45 participants 41 participants 129 participants
43.5  (7.7) 40.8  (7.45) 39.3  (8.77) 41.2  (8.09)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 45 participants 41 participants 129 participants
Female
10
  23.3%
7
  15.6%
7
  17.1%
24
  18.6%
Male
33
  76.7%
38
  84.4%
34
  82.9%
105
  81.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 43 participants 45 participants 41 participants 129 participants
43 45 41 129
1.Primary Outcome
Title PANSS-EC Change From Baseline
Hide Description The Positive and Negative Syndrome Scale–Excited Component (PANSS–EC) comprises 5 items associated with agitation: poor impulse control, tension, hostility, uncooperativeness, and excitement; each scored 1 (min) to 7 (max). The PANSS-EC, the sum of these 5 subscales, thus ranges from 5 to 35. Individuals were eligible if they had a PANSS-EC of ≥14 (out of 35) and a score ≥4 (out of 7) on at least 1 of the 5 items.
Time Frame 2 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
The ITT population consisted of all patients who took any study medication and had both baseline data and at least 1 efficacy assessment after the. Any observation recorded after the use of rescue medication was censored and subject to the last observation carried forward algorithm.
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description:
Inhaled Staccato Placebo, single dose
Inhaled Staccato Loxapine 5 mg, single dose
Inhaled Staccato Loxapine 10 mg, single dose
Overall Number of Participants Analyzed 43 45 41
Mean (Standard Deviation)
Unit of Measure: PANSS units
-4.98  (4.13) -6.71  (5.14) -8.56  (4.9)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0880
Comments p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
Method ANCOVA
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
Method ANCOVA
Comments [Not Specified]
2.Secondary Outcome
Title BARS Change From Baseline After Drug Treatment
Hide Description Change from baseline on the Behavioral Activity Rating Scale (BARS) ranging from 1 to 7 where: 1 = difficult or unable to rouse, 2 = asleep but responds normally to verbal or physical contact, 3 = drowsy, appears sedated, 4 = quiet, and awake (normal level of activity), 5 = signs of overt (physical or verbal) activity, calms down with instructions, 6 = extremely or continuously active, not requiring restraint, 7 = violent, requires restraint.
Time Frame 2 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients receiving experimental treatment
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description:
Inhaled Staccato Placebo, single dose
Inhaled Staccato Loxapine 5 mg, single dose
Inhaled Staccato Loxapine 10 mg, single dose
Overall Number of Participants Analyzed 43 45 41
Mean (Standard Deviation)
Unit of Measure: BARS Score, Change from Baseline, units
-0.930  (0.936) -1.53  (1.38) -2.02  (1.35)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0583
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value < 0.0001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
3.Secondary Outcome
Title Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration
Hide Description Clinical Global Impression- Improvement (CGI-I) scores ranged from 1 to 7: 0=not assessed (missing), 1=very much improved, 2=much improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=much worse, 7=very much worse.
Time Frame 2 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients receiving treatment
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description:
Inhaled Staccato Placebo, single dose
Inhaled Staccato Loxapine 5 mg, single dose
Inhaled Staccato Loxapine 10 mg, single dose
Overall Number of Participants Analyzed 43 45 40
Mean (Standard Deviation)
Unit of Measure: CGI-I Units (7=worse, 1=better)
3.19  (0.932) 2.53  (1.10) 2.28  (1.18)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0067
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0003
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
4.Secondary Outcome
Title CGI-I Responders
Hide Description Frequency of response based on the CGI-I (defined as achieving a CGI-I score of 1 or 2 at 2 hours after administration of the inhalation)
Time Frame 2 hours
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients treated
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description:
Inhaled Staccato Placebo, single dose
Inhaled Staccato Loxapine 5 mg, single dose
Inhaled Staccato Loxapine 10 mg, single dose
Overall Number of Participants Analyzed 43 45 40
Measure Type: Count of Participants
Unit of Measure: Participants
9
  20.9%
22
  48.9%
25
  62.5%
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 5 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0076
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Inhaled Placebo, Inhaled Loxapine 10 mg
Comments [Not Specified]
Type of Statistical Test Superiority
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0001
Comments [Not Specified]
Method Fisher Exact
Comments [Not Specified]
Time Frame From informed consent through 30 days after last treatment
Adverse Event Reporting Description Adverse events observed by the Investigator or study personnel during study assessments or when volunteered by the patient were recorded on the Adverse Event CRF. The severity of the AE and relationship to study drug was determined by the investigator. Medications used to treat the adverse event were recorded on the Concomitant Medication CRF.
 
Arm/Group Title Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Hide Arm/Group Description Inhaled Staccato Placebo, single dose Inhaled Staccato Loxapine 5 mg, single dose Inhaled Staccato Loxapine 10 mg, single dose
All-Cause Mortality
Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/43 (0.00%)      0/45 (0.00%)      0/41 (0.00%)    
Show Serious Adverse Events Hide Serious Adverse Events
Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   1/43 (2.33%)      1/45 (2.22%)      1/41 (2.44%)    
Injury, poisoning and procedural complications       
Overdose * 1 [1]  1/43 (2.33%)  1 0/45 (0.00%)  0 0/41 (0.00%)  0
Psychiatric disorders       
Exacerbation of schizophrenia * 1 [2]  0/43 (0.00%)  0 0/45 (0.00%)  0 1/41 (2.44%)  1
Vascular disorders       
Worsening of hypertension * 1 [3]  0/43 (0.00%)  0 1/45 (2.22%)  1 0/41 (0.00%)  0
1
Term from vocabulary, MedDRA (version 8.0)
*
Indicates events were collected by non-systematic assessment
[1]
A 43 year-old white male with a history of schizophrenia and intravenous drug abuse (heroin and cocaine) randomized to receive placebo, was found dead on the bathroom floor next to an empty syringe 6 days after treatment.
[2]
A 23 year-old male with schizophrenia, randomized to receive Loxapine 10 mg, was hospitalized 14 days later for exacerbation of schizophrenia, agitation, noncompliance with medication taking and response to internal stimuli.
[3]
A 48 year-old m with schizophrenia on treatment for hypertension received Loxapine 5 mg. While being followed up as an out-patient (11 days later), he developed worsening hypertension (BP 210/130), was hospitalized, treated, and D/C the next day
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Inhaled Placebo Inhaled Loxapine 5 mg Inhaled Loxapine 10 mg
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   14/43 (32.56%)      14/45 (31.11%)      16/41 (39.02%)    
Gastrointestinal disorders       
Dysgeusia * 1  4/43 (9.30%)  4 2/45 (4.44%)  2 7/41 (17.07%)  7
Nervous system disorders       
Dizziness * 1  4/43 (9.30%)  4 5/45 (11.11%)  5 2/41 (4.88%)  2
Headache * 1  1/43 (2.33%)  1 2/45 (4.44%)  2 5/41 (12.20%)  5
Sedation * 1  6/43 (13.95%)  6 6/45 (13.33%)  6 9/41 (21.95%)  9
1
Term from vocabulary, MedDRA 8.0
*
Indicates events were collected by non-systematic assessment
Because of the need to provide informed consent, the types of patients enrolled in the study may not have been representative of the most severely agitated patients who present for emergency care.
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
Name/Title: Executive VP, Research & Development, Regulatory & Quality
Organization: Alexza Pharmaceuticals, Inc
Phone: 650.944.7071
Responsible Party: Alexza Pharmaceuticals, Inc.
ClinicalTrials.gov Identifier: NCT00369577     History of Changes
Other Study ID Numbers: AMDC-004-201
004-201
First Submitted: August 25, 2006
First Posted: August 29, 2006
Results First Submitted: January 30, 2017
Results First Posted: January 2, 2018
Last Update Posted: January 2, 2018