Staccato Loxapine in Agitated Patients With Bipolar Disorder

• Sponsor: Alexza Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00721955
• Collaborator: (none)
• Enrollment: 314
• Locations: 6
• Arms: 3
• Duration (Months): 3
• Patients Per Site: 52.3
• Patients Per Site Per Month: 17.3

Study Details

Study Description

Brief Summary

Phase 3 safety and efficacy study of Staccato Loxapine in the treatment of acute agitation in bipolar 1 disorder patients.

Condition or Disease	Intervention/Treatment	Phase
Bipolar I Disorder	Drug: Inhaled Placebo; Drug: Inhaled loxapine 5 mg; Drug: Inhaled loxapine 10 mg	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: 314 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 Patients With Bipolar I Disorder and Acute Agitation
• Study Start Date: Jul 1, 2008
• Actual Primary Completion Date: Oct 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Change in PANSS Excited Component (PEC) Score From Baseline Following Dose #1 of Staccato Loxapine, Compared With Placebo [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 Following Dose #1 of Staccato Loxapine, Compared With Placebo [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 bipolar 1 disorder 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	Synergy Escondido	Escondido	California	United States	92025
2	Collaborative NeuroScience Network, Inc.	Garden Grove	California	United States	92845
3	Atlanta Center for Medical Research	Atlanta	Georgia	United States	30308
4	FutureSearch Trials	Austin	Texas	United States	78756
5	Claghorn-Lesem Research Clinic	Houston	Texas	United States	77008
6	Northwest Clinical Research Center	Bellevue	Washington	United States	98004

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

• Kwentus J, Riesenberg RA, Marandi M, Manning RA, Allen MH, Fishman RS, Spyker DA, Kehne JH, Cassella JV. Rapid acute treatment of agitation in patients with bipolar I disorder: a multicenter, randomized, placebo-controlled clinical trial with inhaled loxapine. Bipolar Disord. 2012 Feb;14(1):31-40. doi: 10.1111/j.1399-5618.2011.00975.x.

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00721955
• Other Study ID Numbers: AMDC-004-302
• First Posted: Jul 25, 2008
• Last Update Posted: Jul 26, 2017
• Last Verified: Oct 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.: Bipolar 1 disorder,; agitation,; acute,; treatment
• Additional relevant MeSH terms: Disease; Loxapine

Study Results

Participant Flow

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2
Period Title: Overall Study
STARTED	105	104	105
COMPLETED	105	104	103
NOT COMPLETED	0	0	2

Baseline Characteristics

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg	Total
Arm/Group Description	Inhaled Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2	Total of all reporting groups
Overall Participants	105	104	105	314
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	105 100%	104 100%	105 100%	314 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	40.6 (9.82)	41.2 (9.63)	40.5 (9.80)	40.7 (9.72)
Sex: Female, Male (Count of Participants)
Female	49 46.7%	57 54.8%	52 49.5%	158 50.3%
Male	56 53.3%	47 45.2%	53 50.5%	156 49.7%
Region of Enrollment (participants) [Number]
United States	105 100%	104 100%	105 100%	314 100%

Outcome Measures

1. Primary Outcome

Title	Change in PANSS Excited Component (PEC) Score From Baseline Following Dose #1 of Staccato Loxapine, Compared With Placebo
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 Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2
Measure Participants	105	104	105
Mean (Standard Deviation) [units on a scale]	-4.9 (4.77)	-8.1 (4.90)	-9.0 (4.67)

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	<0.0001
	Comments	p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
	Method	ANCOVA
	Comments

Statistical Analysis 2

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

2. Secondary Outcome

Title	Clinical Global Impression-Improvement (CGI-I) Score Following Dose #1 of Staccato Loxapine, Compared With Placebo
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 Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2
Measure Participants	105	104	105
Mean (Standard Deviation) [units on a scale]	3.0 (0.99)	2.1 (1.10)	1.9 (1.14)

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	<0.0001
	Comments	p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
	Method	ANCOVA
	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	-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
	Method	ANCOVA
	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 Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2	Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2
Measure Participants	105	104	105
Count of Participants [Participants]	29 27.6%	69 66.3%	78 74.3%

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 Staccato Placebo, may repeat after 2 hours x 2 Inhaled Placebo: Inhaled loxapine Placebo, may repeat after 2 hours x 2		Inhaled Staccato Loxapine 5 mg, may repeat after 2 hours x 2 Inhaled loxapine 5 mg: Inhaled Staccato loxapine 5 mg, may repeat after 2 hours x 2		Inhaled Staccato Loxapine 10 mg, may repeat after 2 hours x 2 Inhaled loxapine 10 mg: Inhaled Staccato loxapine 10 mg, may repeat after 2 hours x 2
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	0/105 (0%)		0/104 (0%)		0/105 (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	0/105 (0%)		0/104 (0%)		0/105 (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	26/105 (24.8%)		35/104 (33.7%)		31/105 (29.5%)
Gastrointestinal disorders
Dysgeusia	6/105 (5.7%)	6	18/104 (17.3%)	18	18/105 (17.1%)	18
Musculoskeletal and connective tissue disorders
Headache	9/105 (8.6%)	9	4/104 (3.8%)	4	2/105 (1.9%)	2
Nervous system disorders
Dizziness	8/105 (7.6%)	8	6/104 (5.8%)	6	5/105 (4.8%)	5
Sedation	3/105 (2.9%)	3	7/104 (6.7%)	7	6/105 (5.7%)	6

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.

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. The sponsor cannot require changes to the communication and cannot extend the embargo.