Staccato Loxapine in Agitation (Proof of Concept)

• Sponsor: Alexza Pharmaceuticals, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00369577
• Collaborator: (none)
• Enrollment: 129
• Location: 1
• Arms: 3
• Duration (Months): 5
• Patients Per Site Per Month: 25.7

Study Details

Study Description

Brief Summary

The purpose of this study is to assess efficacy and safety of Staccato Loxapine in the treatment of acute agitation in schizophrenic patients. The study will be conducted in 120 agitated schizophrenic patients - either newly admitted to a hospital setting or a research unit for acute agitation or already in hospital for chronic underlying conditions. Patients meeting entry criteria will be randomized to one of two doses of Staccato Loxapine or to Staccato Placebo. Following administration of study drug, assessment of agitation state will be conducted at serial time points using standard agitation scales over a 24 hour period.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia	Drug: Inhaled Placebo; Drug: Inhaled Loxapine 5 mg; Drug: Inhaled Loxapine 10 mg	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 129 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, Single Dose Efficacy and Safety Study of StaccatoTM Loxapine for Inhalation in Schizophrenic Patients With Agitation.
• Study Start Date: Aug 1, 2006
• Actual Primary Completion Date: Jan 1, 2007
• Actual Study Completion Date: Jan 1, 2007

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Inhaled Placebo Inhaled Staccato Placebo, single dose	Drug: Inhaled Placebo; Inhaled Placebo, single dose; Other Names: Staccato Loxapine Placebo
Experimental: Inhaled Loxapine 5 mg Inhaled Staccato Loxapine 5 mg, single dose	Drug: Inhaled Loxapine 5 mg; Inhaled Staccato Loxapine 5 mg, single dose; Other Names: Inhaled Staccato Loxapine 5 mg ADASUVE 5 mg
Experimental: Inhaled Loxapine 10 mg Inhaled Staccato Loxapine 10 mg, single dose	Drug: Inhaled Loxapine 10 mg; Inhaled Staccato Loxapine 10 mg, single dose; Other Names: Inhaled Staccato Loxapine 10 mg ADASUVE 10 mg

Outcome Measures

Primary Outcome Measures

1. PANSS-EC Change From Baseline [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. BARS Change From Baseline After Drug Treatment [2 hours]

   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.

2. Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration [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.

3. CGI-I Responders [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:

1. Male and female patients between the ages of 18 to 65 years, inclusive.

2. Patients who have met DSM-IV criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder.

3. Patients who are judged to be clinically agitated at Baseline with a total score of ≥ 14 on the 5 items (poor impulse control, tension, hostility, uncooperativeness, and excitement) comprising the PANSS Excited Component (PEC).

4. Patients who have a value of ≥ 4 (out of 7) on at least 1 of the 5 items on the PANSS Excited Component.

5. Patients who read and understand English and provide written informed consent.

6. Patients who are in good general health prior to study participation as determined by a detailed medical history, physical examination, 12-lead ECG, blood chemistry profile, hematology, urinalysis and in the opinion of the Principal Investigator.

7. Female participants, if of child-bearing potential and sexually active, and male participants, if sexually active with a partner of child-bearing potential, who agree to use a medically acceptable and effective birth control method throughout the study and for one week following the end of the study. Medically acceptable methods of contraception that may be used by the participant and/or his/her partner include abstinence, birth control pills or patches, diaphragm with spermicide, intrauterine device (IUD), condom with foam or spermicide, vaginal spermicidal suppository, surgical sterilization and progestin implant or injection. Prohibited methods include: the rhythm method, withdrawal, condoms alone, or diaphragm alone.

Exclusion Criteria:

1. Patients with agitation caused by acute intoxication must be excluded. Positive identification of non-prescription drugs during urine screening excludes the subject.

2. Patients treated with benzodiazepines or other hypnotics or oral or short-acting intramuscular antipsychotics within 4 hours prior to study drug administration must be excluded.

3. Patients treated with injectable depot neuroleptics within one dose interval prior to study drug administration must be excluded.

4. Patients with a history of allergic reactions to loxapine or amoxapine must be excluded.

5. Female patients who have a positive pregnancy test at screening or are breastfeeding must be excluded.

6. Patients who have Parkinson's disease, hydrocephalus, seizure disorder, or history of significant head trauma must be excluded.

7. Patients with laboratory or ECG abnormalities considered clinically significant by the investigator or qualified designee that would have clinical implications for the patient's participation in the study must be excluded.

8. Patients with serious and unstable illnesses including current hepatic, renal, gastroenterologic, respiratory, cardiovascular (including ischemic heart disease and congestive heart failure), endocrinologic, neurologic (including stroke, transient ischemic attack, subarachnoidal bleeding, brain tumor, encephalopathy, and meningitis), or hematologic disease must be excluded.

9. Patients who have a history of acute or chronic pulmonary disease that precludes administration of Staccato Loxapine (asthma, bronchitis, emphysema) must be excluded.

10. Patients who have received an investigational drug within 30 days prior to the current agitation episode must be excluded.

11. Patients who are considered by the investigator, for any reason, to be an unsuitable candidate for receiving loxapine, or unable to use the inhalation device, must be excluded.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pacific Clinical Research Medical Group, 1317 West Foothill Blvd, Suite 200,	Upland	California	United States	91786

Sponsors and Collaborators

• Alexza Pharmaceuticals, Inc.

Investigators

• Principal Investigator: Daniel Zimbroff, MD, Pacific Clinical Research Medical Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alexza Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT00369577
• Other Study ID Numbers: AMDC-004-201; 004-201
• First Posted: Aug 29, 2006
• Last Update Posted: Jan 2, 2018
• Last Verified: Jun 1, 2013

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

Study Results

Participant Flow

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 Detail	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
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

Baseline Characteristics

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg	Total
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 Participants	43	45	41	129
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	43 100%	45 100%	41 100%	129 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.5 (7.7)	40.8 (7.45)	39.3 (8.77)	41.2 (8.09)
Sex: Female, Male (Count of 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 (participants) [Number]
United States	43 100%	45 100%	41 100%	129 100%

Outcome Measures

1. Primary Outcome

Title	PANSS-EC Change 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	2 hours

Outcome Measure Data

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
Arm/Group Description	Inhaled Staccato Placebo, single dose	Inhaled Staccato Loxapine 5 mg, single dose	Inhaled Staccato Loxapine 10 mg, single dose
Measure Participants	43	45	41
Mean (Standard Deviation) [PANSS units]	-4.98 (4.13)	-6.71 (5.14)	-8.56 (4.9)

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	0.0880
	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	0.0002
	Comments	p-values (adjusted) using Dunnett's t-test in main effects ANCOVA model
	Method	ANCOVA
	Comments

2. Secondary Outcome

Title	BARS Change From Baseline After Drug Treatment
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

Outcome Measure Data

Analysis Population Description

All patients receiving experimental treatment

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Staccato Placebo, single dose	Inhaled Staccato Loxapine 5 mg, single dose	Inhaled Staccato Loxapine 10 mg, single dose
Measure Participants	43	45	41
Mean (Standard Deviation) [BARS Score, Change from Baseline, units]	-0.930 (0.936)	-1.53 (1.38)	-2.02 (1.35)

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	0.0583
	Comments
	Method	Wilcoxon (Mann-Whitney)
	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	Wilcoxon (Mann-Whitney)
	Comments

3. Secondary Outcome

Title	Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration
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

Outcome Measure Data

Analysis Population Description

All patients receiving treatment

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Staccato Placebo, single dose	Inhaled Staccato Loxapine 5 mg, single dose	Inhaled Staccato Loxapine 10 mg, single dose
Measure Participants	43	45	40
Mean (Standard Deviation) [CGI-I Units (7=worse, 1=better)]	3.19 (0.932)	2.53 (1.10)	2.28 (1.18)

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	0.0067
	Comments
	Method	Wilcoxon (Mann-Whitney)
	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	0.0003
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments

4. 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	2 hours

Outcome Measure Data

Analysis Population Description

All patients treated

Arm/Group Title	Inhaled Placebo	Inhaled Loxapine 5 mg	Inhaled Loxapine 10 mg
Arm/Group Description	Inhaled Staccato Placebo, single dose	Inhaled Staccato Loxapine 5 mg, single dose	Inhaled Staccato Loxapine 10 mg, single dose
Measure Participants	43	45	40
Count of Participants [Participants]	9 20.9%	22 48.9%	25 61%

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	0.0076
	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	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
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 (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/43 (0%)		0/45 (0%)		0/41 (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	1/43 (2.3%)		1/45 (2.2%)		1/41 (2.4%)
Injury, poisoning and procedural complications
Overdose	1/43 (2.3%)	1	0/45 (0%)	0	0/41 (0%)	0
Psychiatric disorders
Exacerbation of schizophrenia	0/43 (0%)	0	0/45 (0%)	0	1/41 (2.4%)	1
Vascular disorders
Worsening of hypertension	0/43 (0%)	0	1/45 (2.2%)	1	0/41 (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	14/43 (32.6%)		14/45 (31.1%)		16/41 (39%)
Gastrointestinal disorders
Dysgeusia	4/43 (9.3%)	4	2/45 (4.4%)	2	7/41 (17.1%)	7
Nervous system disorders
Dizziness	4/43 (9.3%)	4	5/45 (11.1%)	5	2/41 (4.9%)	2
Headache	1/43 (2.3%)	1	2/45 (4.4%)	2	5/41 (12.2%)	5
Sedation	6/43 (14%)	6	6/45 (13.3%)	6	9/41 (22%)	9

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.