Staccato Loxapine in Agitated Patients With Schizophrenia

• Sponsor: Alexza Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00628589
• Collaborator: (none)
• Enrollment: 344
• Location: 1
• Arms: 3
• Duration (Months): 3
• Patients Per Site Per Month: 116.3

Study Details

Study Description

Brief Summary

Phase 3 safety and efficacy study of Staccato Loxapine in the treatment of acute agitation in schizophrenic patients

Condition or Disease	Intervention/Treatment	Phase
Patients With Schizophrenia and Acute Agitation	Drug: Inhaled loxapine 5 mg; Drug: Inhaled loxapine 10 mg; Drug: Inhaled placebo	Phase 3

Detailed Description

This is an in-clinic, multi-center, randomized, double-blind, placebo-controlled study of 2 dose levels of Staccato Loxapine, 5 and 10 mg. Patients may receive up to 3 doses of study drug in a 24-hour period, depending on their clinical status. The primary endpoint is the change from baseline in the PANSS (Positive and Negative Symptom Scale) Excited Component (also known as PEC) score, performed at 2 hours after the first dose.

Study Design

• Study Type: Interventional
• Actual Enrollment: 344 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Multi-Dose Efficacy and Safety Study of Staccato® Loxapine for Inhalation in Schizophrenic Patients With Agitation
• Study Start Date: Feb 1, 2008
• Actual Primary Completion Date: May 1, 2008
• Actual Study Completion Date: May 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Inhaled Loxapine 5 mg Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Drug: Inhaled loxapine 5 mg; Inhaled loxapine 5 mg; Other Names: ADASUVE
Experimental: Inhaled Loxapine 10 mg Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours	Drug: Inhaled loxapine 10 mg; Inhaled loxapine 10 mg; Other Names: ADASUVE
Placebo Comparator: Inhaled placebo Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Drug: Inhaled placebo; Inhaled placebo

Outcome Measures

Primary Outcome Measures

1. Change in PANSS-EC From Baseline [Baseline and 2 hours]

   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.

Secondary Outcome Measures

1. Clinical Global Impression-Improvement (CGI-I) Score [Baseline and 2 hours]

   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.

2. CGI-I Responders [Baseline and 2 hours]

   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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male and female adult patients with schizophrenia and acute agitation

Exclusion Criteria:

• Agitation caused primarily by acute intoxication

• History of drug or alcohol dependence

• Treatment with benzodiazepines or other hypnotics within 4 hours prior to study drug administration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30308

Sponsors and Collaborators

• Alexza Pharmaceuticals, Inc.

Investigators

• Study Director: Robert S Fishman, MD, Alexza Pharmaceuticals, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

• Lesem MD, Tran-Johnson TK, Riesenberg RA, Feifel D, Allen MH, Fishman R, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011 Jan;198(1):51-8. doi: 10.1192/bjp.bp.110.081513.

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00628589
• Other Study ID Numbers: AMDC-004-301
• First Posted: Mar 5, 2008
• Last Update Posted: Jul 26, 2017
• Last Verified: Jun 1, 2008

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Alexza Pharmaceuticals, Inc.: schizophrenia, agitation, inhaled loxapine, ADASUVE
• Additional relevant MeSH terms: Psychomotor Agitation; Schizophrenia; Loxapine

Study Results

Participant Flow

Recruitment Details	The study was conducted at 24 centers - all in the US. Patients recruited for screening were admitted to a hospital or research unit with acute agitation, and were being treated for chronic underlying schizophrenia.
Pre-assignment Detail	During the Pre-treatment Period, agitated schizophrenic patients were screened for inclusion in the study. This period lasted until the evaluations were begun.

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours
Period Title: Overall Study
STARTED	115	116	113
COMPLETED	114	114	110
NOT COMPLETED	1	2	3

Baseline Characteristics

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg	Total
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours	Total of all reporting groups
Overall Participants	115	116	113	344
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	115 100%	116 100%	113 100%	344 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.9 (9.45)	43.2 (10.24)	42.2 (9.82)	43.1 (9.84)
Sex: Female, Male (Count of Participants)
Female	35 30.4%	29 25%	27 23.9%	91 26.5%
Male	80 69.6%	87 75%	86 76.1%	253 73.5%
Region of Enrollment (participants) [Number]
United States	115 100%	116 100%	113 100%	344 100%

Outcome Measures

1. Primary Outcome

Title	Change in PANSS-EC From Baseline
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	Baseline and 2 hours

Outcome Measure Data

Analysis Population Description

ITT Population with LOCF

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours
Measure Participants	115	116	112
Mean (Standard Deviation) [units on a scale]	-5.5 (4.92)	-8.1 (5.17)	-8.6 (4.37)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments	LS mean was used in the primary efficacy analysis
Statistical Test of Hypothesis	p-Value	0.0004
	Comments
	Method	ANCOVA
	Comments	p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments	p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model

2. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Score
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	Baseline and 2 hours

Outcome Measure Data

Analysis Population Description

ITT Population with LOCF

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours
Measure Participants	115	116	112
Mean (Standard Deviation) [units on a scale]	2.8 (1.11)	2.3 (1.24)	2.1 (1.00)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	CGI-I Responders
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	Baseline and 2 hours

Outcome Measure Data

Analysis Population Description

ITT Population with LOCF

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours	Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours
Measure Participants	115	116	112
Count of Participants [Participants]	41 35.7%	66 56.9%	75 66.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 5 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0015
	Comments
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Inhaled Placebo, Inhaled Loxapine 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	From informed consent through 30 days after last treatment
Adverse Event Reporting Description	AEs were recorded when identified by the study center staff or volunteered by a patient.
Arm/Group Title	Inhaled Placebo		Inhaled Loxapine 5 mg		Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Loxapine placebo, may repeat x 1 or 2 after 2 hours		Inhaled Loxapine 5 mg, may repeat x 1 or 2 after 2 hours		Inhaled Loxapine 10 mg, may repeat x 1 or 2 after 2 hours
All Cause Mortality
	Inhaled Placebo		Inhaled Loxapine 5 mg		Inhaled Loxapine 10 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/115 (0%)		0/116 (0%)		0/113 (0%)
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	1/115 (0.9%)		0/116 (0%)		1/113 (0.9%)
Gastrointestinal disorders
Gastroenteritis	0/115 (0%)	0	0/116 (0%)	0	1/113 (0.9%)	1
Psychiatric disorders
Exacerbation of schizophrenia	1/115 (0.9%)	1	0/116 (0%)	0	0/113 (0%)	0
Other (Not Including 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	44/115 (38.3%)		35/116 (30.2%)		41/113 (36.3%)
Gastrointestinal disorders
Dysgeusia	3/115 (2.6%)	3	10/116 (8.6%)	10	12/113 (10.6%)	12
Nausea	6/115 (5.2%)	6	1/116 (0.9%)	1	2/113 (1.8%)	2
Nervous system disorders
Dizziness	11/115 (9.6%)	11	6/116 (5.2%)	6	12/113 (10.6%)	12
Headache	16/115 (13.9%)	16	3/116 (2.6%)	3	3/113 (2.7%)	3
Sedation	11/115 (9.6%)	11	15/116 (12.9%)	15	12/113 (10.6%)	12

Limitations/Caveats

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.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Principal Investigators are NOT employed by the organization sponsoring the study. The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days from the time submitted to the sponsor for review. The sponsor cannot require changes to the communication and cannot extend the embargo.