Schizophrenia
Conditions
Keywords
Agitation, Schizophrenia
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.
Interventions
DRUGInhaled Placebo
Inhaled Placebo, single dose
Inhaled Staccato Loxapine 5 mg, single dose
Inhaled Staccato Loxapine 10 mg, single dose
Sponsors
Alexza Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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) |
Countries
United States
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 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.
Participants by arm
| Arm | Count |
|---|---|
| Inhaled Placebo Inhaled Staccato Placebo, single dose | 43 |
| Inhaled Loxapine 5 mg Inhaled Staccato Loxapine 5 mg, single dose | 45 |
| Inhaled Loxapine 10 mg Inhaled Staccato Loxapine 10 mg, single dose | 41 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Inhaled Loxapine 5 mg | Inhaled Loxapine 10 mg | Inhaled Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 41 Participants | 43 Participants | 129 Participants |
| Age, Continuous | 40.8 years STANDARD_DEVIATION 7.45 | 39.3 years STANDARD_DEVIATION 8.77 | 43.5 years STANDARD_DEVIATION 7.7 | 41.2 years STANDARD_DEVIATION 8.09 |
| Region of Enrollment United States | 45 participants | 41 participants | 43 participants | 129 participants |
| Sex: Female, Male Female | 7 Participants | 7 Participants | 10 Participants | 24 Participants |
| Sex: Female, Male Male | 38 Participants | 34 Participants | 33 Participants | 105 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 43 | 0 / 45 | 0 / 41 |
| other Total, other adverse events | 14 / 43 | 14 / 45 | 16 / 41 |
| serious Total, serious adverse events | 1 / 43 | 1 / 45 | 1 / 41 |
Outcome results
Primary
PANSS-EC Change From Baseline
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
Population: 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 | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | PANSS-EC Change From Baseline | -4.98 PANSS units | Standard Deviation 4.13 |
| Inhaled Loxapine 5 mg | PANSS-EC Change From Baseline | -6.71 PANSS units | Standard Deviation 5.14 |
| Inhaled Loxapine 10 mg | PANSS-EC Change From Baseline | -8.56 PANSS units | Standard Deviation 4.9 |
p-value: 0.088ANCOVA
p-value: 0.0002ANCOVA
Secondary
BARS Change From Baseline After Drug Treatment
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
Population: All patients receiving experimental treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | BARS Change From Baseline After Drug Treatment | -0.930 BARS Score, Change from Baseline, units | Standard Deviation 0.936 |
| Inhaled Loxapine 5 mg | BARS Change From Baseline After Drug Treatment | -1.53 BARS Score, Change from Baseline, units | Standard Deviation 1.38 |
| Inhaled Loxapine 10 mg | BARS Change From Baseline After Drug Treatment | -2.02 BARS Score, Change from Baseline, units | Standard Deviation 1.35 |
p-value: 0.0583Wilcoxon (Mann-Whitney)
p-value: <0.0001Wilcoxon (Mann-Whitney)
Secondary
CGI-I Responders
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
Population: All patients treated
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Inhaled Placebo | CGI-I Responders | 9 Participants |
| Inhaled Loxapine 5 mg | CGI-I Responders | 22 Participants |
| Inhaled Loxapine 10 mg | CGI-I Responders | 25 Participants |
p-value: 0.0076Fisher Exact
p-value: 0.0001Fisher Exact
Secondary
Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration
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
Population: All patients receiving treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Inhaled Placebo | Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration | 3.19 CGI-I Units (7=worse, 1=better) | Standard Deviation 0.932 |
| Inhaled Loxapine 5 mg | Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration | 2.53 CGI-I Units (7=worse, 1=better) | Standard Deviation 1.1 |
| Inhaled Loxapine 10 mg | Clinical Global Impressions-Improvement Scale (CGI-I) After Drug Administration | 2.28 CGI-I Units (7=worse, 1=better) | Standard Deviation 1.18 |
p-value: 0.0067Wilcoxon (Mann-Whitney)
p-value: 0.0003Wilcoxon (Mann-Whitney)