Conditions: Agitation,Psychomotor Haloperidol Causing Adverse Effects in Therapeutic Use Lorazepam Causing Adverse Effects in Therapeutic Use Loxapine Causing Adverse Effects in Therapeutic Use
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 2
Healthy volunteers: yes

Brief summary:
The primary objective of this study is to determine the noninferiority of inhaled loxapine compared to intramuscular haloperidol/lorazepam on agitation reduction at 120 minutes.

Detailed description:
The primary objective of this study is to determine the noninferiority of inhaled loxapine compared to intramuscular haloperidol/lorazepam on agitation reduction at 120 minutes.

Arms:
arm 1: IM haloperidol 5mg + IM lorazepam 2mg + placebo inhaler arm 2: Inhaled loxapine 10mg + IM normal saline

Interventions: intervention 1: Haloperidol + lorazepam intervention 2: Loxapine
Intervention descriptions: intervention 1: Haloperidol + lorazepam + placebo intervention 2: loxapine + placebo

Protocol document:
Prot_SAP_000.pdf: 
Version #: 11 
Date: 10/18/17 
Page 1 
 
 
 
 
Study Title: 
A randomized double-blind multicenter double-dummy non-inferiority 
trial of inhaled loxapine and intramuscular haloperidol + lorazepam for 
the reduction of agitation 
 
Principal Investigator:  
Michael Wilson 
 
University of Arkansas for Medical Sciences 
  
4301 W. Markham Street, Slot # 584 
Little Rock, AR 72205 
Telephone: 501-686-5515 
Email: MPWilson@uams.edu 
 
 
Sub-Investigator (s): 
Rawle Seupaul 
 
Department of Emergency Medicine 
University of Arkansas for Medical Sciences 
4301 W. Markham Street, Slot # 584 
Little Rock, AR 72205 
Telephone: 501-686-5515 
Email: RASeupaul@uams.edu 
 
 
Carly Eastin 
 
University of Arkansas for Medical Sciences 
  
4301 W. Markham Street, Slot # 584 
Little Rock, AR 72205 
Telephone: 501-686-5515 
Email: CDEastin@uams.edu 
 
 
Study location: 
UAMS 
 
 
 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 2 
 
Background and Rationale 
Scientific rationale: Agitation is dangerous   
Agitation, and its more serious form, physical violence, is a frequent problem in the emergency 
department. In a 2011 study by the Emergency Nurses’ Association, more than half of all nurses reported 
physical or verbal assault in the previous 7 days. Agitation is life-threatening both for clinicians and for 
patients (Zeller et al 2014). The control of agitation is therefore of extreme importance in the emergency 
setting, and emergency clinicians often place great importance on medications which result in quick 
calming. 
 
Despite an emerging national consensus over the use of oral or inhaled medications, emergency 
departments nationwide have been slow to adopt their use (Wilson et al 2014). This may be in part 
because there is limited data about the use of oral medications in the typical adult/pediatric emergency 
department. Additionally, the use of intramuscular haloperidol and droperidol are common in emergency 
departments nationwide (Campillo et al 2015). The safety of haloperidol has been confirmed with 40+ 
years of clinical practice and numerous publications. Thus, the continued use of IM haloperidol and IM 
droperidol in emergency departments occurs because educated clinicians, who are familiar with the extant 
literature in their specialty, believe that these medications are preferred. The fact that haloperidol is not a 
preferred medication long-term in the outpatient setting does not seem to impact its use acutely in the 
emergency department. 
 
The study proposed below attempts to test intramuscular haloperidol/lorazepam against inhaled loxapine 
in the reduction of agitation associated with psychiatric illness. Adasuve® is an insufflation system 
designed to provide 10mg of loxapine to a patient. Although the use of this medication is not as wide-
spread as haloperidol, loxapine is an FDA-approved medication which is thought to have two advantages: 
faster onset of action and no need for needlestick. 
 
Hypothesis & Specific Aims 
The hypothesis of this study is that inhaled loxapine is non-inferior to intramuscular 
haloperidol/lorazepam in the reduction of agitation at 120 minutes. 
 
Study Design and Procedures 
Please see Figure 1 for a schematic of study flow. Please note that this study utilizes a double-blind 
double-dummy design with haloperidol and lorazepam in separate syringes, and neither the subjects nor 
the study team will know which patient is assigned to which group. UAMS investigational pharmacy will 
be involved in both the randomization process and preparation of placebo. 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 3 
 
 
Figure 1. Study flow. 
 
In brief, patients who are preconsented for the study (see below), who have a consent from a valid 
surrogate in the ED (see below), or who have mild agitation and are able to consent (see below), and who 
additionally meet all inclusion/exclusion criteria as assessed by a REDCap questionnaire containing 
questions about health and allergies, will be randomized into the study. In this study, patients will be 
administered either a placebo loxapine inhaler + an injection of intramuscular (IM) haloperidol 
5mg/lorazepam 2mg or inhaled loxapine (loxapine) + intramuscular (IM) normal saline. Patient agitation 
will be rated using the Positive And Negative Syndrome Scale-Excited Component (PANSS-EC) and 
Agitation-Calmness Evaluation Scale (ACES) at 5, 10, 15, 20, 30, 45, 60, 90, 120, and 150 minutes. 
Physicians will be allowed to prescribe any other medications that they feel are in the best interest of their 
patient after 5 minutes. After disposition from the emergency department (ED), research staff will view 
the electronic medical record to calculate lengths of stay, admission rates, and additional calming 
medications ordered by physicians. 
 
Study medications will be placed in the ED Pyxis for easy access, and will be labeled only as “study 
drug” in sequentially-numbered opaque sealed envelopes. This process will be performed by UAMS 
pharmacy (please see medications/test articles section below). 
 
Primary outcome/hypothesis 
• Inhaled loxapine is not inferior to IM haloperidol/lorazepam in the reduction of agitation at 120 minutes. 
 
Secondary outcome/hypothesis 
• Inhaled loxapine is associated with shorter lengths of stay, less associated restraint use, fewer admission 
rates, fewer adverse events/side effects, shorter time to administration of study medication, more patients 
calmed by 20 minutes, and less additional calming medication ordered by clinicians. 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 4 
 
Medications/Test articles 
This protocol proposes to test 3 medications: injected haloperidol, injected lorazepam, and inhaled 
loxapine. 
 
Justification of comparator drugs (haloperidol/lorazepam):The use of haloperidol and droperidol is 
standard in EDs 
     In part because of the lack of evidence about other types of anti-agitation drugs in general (and inhaled 
loxapine in particular) in emergency settings, IM haloperidol + lorazepam is widely used in emergency 
departments nationwide (Campillo et al 2015; Wilson et al 2015). The safety of haloperidol has been 
confirmed with 40+ years of clinical practice and numerous publications (see for instance Clinton et al 
1987; Raveendran et al 2007). In addition, both haloperidol and droperidol are thought by many EM 
physicians to be the safest medications in agitated emergency department patients. In part, this is because 
undifferentiated agitation in the ED often has a non-psychiatric or dual-diagnosis cause. If this is true, ED 
clinicians must often choose an appropriate agent carefully, since many types of antipsychotics may 
interact with certain ingested substances. 
     Thus, the continued use of IM haloperidol in emergency departments occurs because educated 
clinicians, who are familiar with the extant literature in their specialty, believe that 1) oral meds are 
inappropriate for severely agitated patients (which anecdotally is thought to represent the only type of 
agitated patient seen in the ED); and 2) haloperidol may be safer antipsychotics acutely given their lack of 
interaction with multiple receptor types. The fact that haloperidol is not a preferred medication long-term 
in the outpatient setting does not seem to impact its use acutely in the emergency department. 
 
     The study medications were chosen after careful thought for a number of reasons: 
 
(1) IM haloperidol has been used in clinical practice for >40 years. There are numerous studies citing 
both safety and efficacy. Haloperidol mainly interacts with the D2 receptor, and has few actions at other 
receptor subtypes. This first-generation antipsychotic (or FGA) is the most common emergency 
department antipsychotic nationwide. Haloperidol is an FDA-approved medication, although it carries a 
black-box warning for use in elderly dementia-related psychosis and carries a warning about use 
intravenously. 
 
(2) IM lorazepam has been used extensively in clinical practice in emergency medicine. It has a relatively 
short half-life (10-20 hours), highly protein bound, is glucuronidated by the liver to lorazepam 
glucuronide, an inactive metabolite, and has virtually no drug-drug interactions. When used in 
combination with haloperidol, it reduces the side effects of haloperidol use alone (Battaglia et al 1997). 
Lorazepam is FDA-approved for treating agitation. 
 
(3) Inhaled loxapine is a recently FDA-approved medication for treating agitation associated with 
schizophrenia or bipolar disorder. Loxapine is a first-generation antipsychotic, is in the pharmaceutical class 
dibenzoxazepine, has affinity for D1/D2/D4 receptors, and has a plasma half-life of approximately 4 hours 
(Nordstrom & Allen 2013). There have been 5 studies to date on the effectiveness of inhaled loxapine 
(Adasuve®) which show efficacy in psychiatric patients (de Berardis et al 2017). However, there have been 
no studies of this medication in the emergency department. Theoretically, inhaled loxapine is thought to be 
more patient-friendly, as it does not require injection in an uncooperative patient. 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 5 
 
Please note that all medications will be bought by pharmacy and shipped directly to this department. The 
randomization and randomization scheme will also be performed by investigational pharmacy. Placebo 
inhalers will be provided by Alexza Pharmaceuticals. 
 
Study Population 
Please see Figure 1 (study flow). Approximately 140 patients will need to be enrolled between two sites. 
We expect anywhere between 70-140 patients to be enrolled at UAMS. As this study utilizes preconsent 
in the outpatient setting (please see below), it is currently unknown how many patients will need to be 
consented before coming to the emergency department with agitation. Conservatively, we expect to 
consent approximately 6000-7000 patients since many of these patients will never subsequently require 
treatment in an emergency department. 
 
With permission of UAMS psychiatry, patients will be approached in the UAMS outpatient mental health 
clinic or Psychiatric Research Institute. Study staff will only approach patients if the medical director 
gives permission, and patients do not object. Patients will be identified using the electronic medical 
record in a manner similar to the emergency department (see below). Furthermore, study staff will only 
approach patients in a private area of the emergency department or Psychiatric Research Institute in order 
to preserve patient confidentiality. In the UAMS emergency department, research assistants may approach 
patients for screening who have been placed in private rooms. Additionally, research assistants may scan 
the trackboard and triage screen to identify patients with chief complaints of a psychiatric nature. Patients 
will be asked to consent for this study should they ever find themselves agitated in the UAMS emergency 
department and in need of emergency medication. Patients who are critically ill or who are unable to be 
consented for any other reason will not be approached. Patients will only be approached after evaluation 
by the treating team, but in order to avoid overly burdening clinical staff who are typically dealing with 
many critically-ill patients, may be approached without treating providers first discussing the study. 
Adults who are visiting a patient may also be consented for the study if they have been a patient at UAMS 
before (as evidenced by a medical record number), meet all inclusion criteria, and express an interest in 
being screened without being asked while in the room with the patient.  
 
Consents will be kept on file with the study, with an expiration date of 3 years from date of signing, and 
are revocable by the patient at any time before administration of medication. Given the expiration date on 
consents, it is possible that a patient who was not 65 at time of consent might have their 65th birthday 
before the consent expires (see inclusion/exclusion criteria below). Consequently, we will limit 
preconsents to patients 62 years or less. (Please note that earlier versions of the research plan asked for a 
one-year expiration date on consent forms. However, given that the study will last at least 2 years, this 
would mean that some patients would need to be reconsented during the course of the study in addition to 
being reconsented at time of enrollment. This is therefore not feasible for this study.) 
 
If patients arrive in the emergency department without a valid consent, they may be approached for 
consent if the agitation is mild enough to allow for the complicated process of true informed consent and 
if they meet all other inclusion/exclusion criteria. If they are too agitated for this, they may be enrolled in 
the study if there is a valid surrogate present in the emergency department. In Arkansas, a valid surrogate 
consists of (in order): a legal power of attorney; a spouse unless legally separated; an adult child; a parent; 
or an adult sibling. Surrogate consent will not be obtained during the pre-consent process; surrogates will 
only provide consent for emergency department patients immediately prior to medication administration 
and observation. 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 6 
 
Please note that if the patient objects to being in the study, a patient’s surrogate objects to being in the 
study, or if the patient's physician objects to the patient being in the study, the patient will not be 
randomized and enrolled, even if previously consented. As the patient’s treating physician is responsible 
for ordering all medications, including study drugs, physicians may elect at their discretion not to order 
one of the randomized drug kits as prepared by the investigational pharmacy. Should the patient’s treating 
physician object after the medication has been ordered & administered, they will be responsible for 
making their objection known to the observing RA, who will cease all observation of the patient and 
withdraw him or her from the study. 
 
Please note that physicians and nursing staff will be notified when the study is ongoing with posted flyers. 
These will be posted in physician & nursing workspaces. Please note that these do not constitute 
advertising for the study, but serve as provider notification in a busy environment in a way that is not 
otherwise feasible. The flyers will contain the PI name & notification number as requested by the IRB. 
However, they will not contain information that is not relevant to treating clinicians, ie, the numerous 
inclusion & exclusion criteria. These will be verbally communicated to clinicians by study staff if the 
need arises. 
 
Inclusion Criteria 
• 
Requires treatment for agitation in judgement of a physician (ie, will place an order for study 
medication in the medical record) 
• 
Patient either pre-consented, with surrogate consent, or able to consent 
• 
Patients between 18 & 64 years of age inclusive (or age 62 at time of consent) 
• 
Patients with known or presumed schizophrenia or bipolar 1 disorder. 
 
Exclusion Criteria 
• 
Patients with acute respiratory signs/symptoms (eg wheezing) 
• 
Known diagnosis of COPD or asthma, or taking meds for asthma or COPD 
• 
Female patients that are obviously pregnant or breast-feeding 
• 
Medically unstable patients 
• 
Patients or surrogates who object to being in the study (even if previously pre-consented) 
• 
Physician objection to patient enrollment in the study for any reason 
• 
Prisoners 
• 
Known diagnosis of Parkinson’s disease 
• 
Known diagnosis of acute narrow-angle glaucoma 
• 
History of toxic central nervous system depression or comatose states 
• 
Known hypersensitivities to loxapine, amoxapine, haloperidol, lorazepam, or any 
benzodiazepines 
• 
History of seizures or conditions that lower the seizure threshold 
 
Risks and Benefits 
The main potential risk to study participants is in loss of confidentiality. Measures to protect the 
confidentiality of study participants will be implemented as described in the Data Handling and 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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Date: 10/18/17 
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Recordkeeping section below. 
 
There are of course also potential adverse reactions to study medications, and these will be described in 
the consent form. In this regard, however, the risk to patients as a part of research is not greater than if 
these patients received the same medications as part of normal clinical care. All medications are FDA-
approved, and it is currently unknown whether one medication combination offers advantages over the 
other. 
 
Risks described in consent form for loxapine: allergic reaction, hypersensitivity, wheezing/bronchospasm 
in patients with COPD or asthma, increased chance of death or stroke over 65, low blood pressure, 
passing out, seizures, impairment of thinking/motor skills, urinary retention. Loxapine is not approved for 
use in pregnancy or in elderly patients with dementia-related psychosis. Please note that elderly dementia-
related psychosis is not listed as an exclusion criterion because patients over the age of 64 are already 
excluded from the study. Major depressive disorder with psychotic features is not listed as an exclusion 
criterion because it is not contraindicated in the prescribing information for inhaled loxapine. In addition, 
patients with major depressive disorder are not being recruited for this study. The information contained 
in the black box warning below is also outlined in the consent form in less technical language. 
 
Risks described in consent form for haloperidol/lorazepam: allergic reaction, increased chance of death or 
stroke if over 65, QT prolongation, increased motor movements/abnormal contractions of muscles, 
increased chance of pneumonia, impairment of thinking/motor skills, possible disturbance of white blood 
cells, fast heart rate, or worsening of glaucoma (if the patient has this disease). These medications are not 
approved for use in pregnancy or in elderly patients with dementia-related psychosis. A black box 
warning for patients with the the latter condition is shown below: 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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Date: 10/18/17 
Page 8 
 
 
 
All study medications are not approved in patients that are pregnant. The potential risk to the fetus will be 
described in detail in the consent form. In the emergency department, ED clinicians typically use a 
combination of either self-report or urine pregnancy test to exclude pregnancy, depending on the urgency 
of treatment. This protocol will use a similar strategy, as ED physicians must agree to treatment by 
placing an order for study medication in the electronic medical record. 
 
If patients require treatment for agitation, there may be a potential direct benefit to the study participants 
as both study medications are thought to prevent harm to both patients and staff. In addition, knowledge 
gained from the study could potentially benefit patients in the future. 
 
Safety assessment section 
 
Research staff will be trained to adhere to the “Steps for Safe Use of Adasuve” as developed for the Risk 
Evaluation and Mitigation Strategy (REMS Program). Please note that some of these steps will be 
performed at time of screening and consent, and some will be performed at time of enrollment: 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 9 
 
 
 
Research staff will report any unusual or adverse events to the treating physician and PI immediately. 
Patients may be terminated from the study either based on the judgment of the treating physician or the 
PI. 
 
A serious adverse event is defined as one where the patient is seriously injured; the staff is seriously 
injured; there is airway compromise requiring intubation; or neuroleptic malignant syndrome. All serious 
adverse events will be reported to the IRB following applicable guidelines for doing so. Serious adverse 
events will be reported to the sponsor, and will be reported to the FDA as required. 
 
Formal oversight of the study will rest with the PI and a data safety monitoring board. The DSMB will be 
convened through the UAMS Translational Research Institute (or TRI). Stopping rules and meeting 
frequency will be designed by the study statistician. 
 
Data Handling and Recordkeeping 
The Principal Investigator and a data safety monitoring board will carefully monitor study procedures to 
protect the safety of research subjects, the quality of the data, and the integrity of the study. All study 
subject material will be assigned a unique identifying code or number in REDCap. The key to the code 
will be kept in a locked file in the principal investigator’s office. Only Dr Wilson, the DSMB, study 
statistician, and select study staff will have access to the code and information that identifies the subject in 
this study. 
 
Records will be maintained for 7 years per IRB requirements. At the discretion of the PI, records may be 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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Date: 10/18/17 
Page 10 
 
scanned and maintained in electronic format instead of paper format once the study is complete. If so, 
electronic records will be audited to ensure high fidelity with the originals. These electronic copies will 
also be maintained on secure password-protected UAMS servers. When eventually destroyed, copies will 
be shredded per UAMS disposal guidelines. 
 
Data collection will be performed through Research Electronic Data Capture (REDCap), and is being set 
up in cooperation with the UAMS Translational Research Institute (TRI) in order to assure 21 CFR Part 
11 and HIPAA compliance. The Hennepin site will be given access to the REDCap collection forms 
through TRI, and the Hennepin data will be accessed by UAMS researchers through this mechanism. 
 
Data Analysis 
The primary outcome for this study will be the non-inferiority of inhaled loxapine compared to IM 
haloperidol + lorazepam on the reduction of agitation at 2 hours using the PANSS-EC scale.The authors 
recognize the three main sources of statistical uncertainty outlined in the FDA guidelines on NI trials: the 
constancy assumption (effect size estimates from the current study are in line with past studies), 
maintaining a fixed type I error rate, and calculating an accurate estimate of the historical evidence of 
sensitivity to drug effect (HESDE). Constancy of the effect of haloperidol + lorazepam has been 
demonstrated in the Cochrane meta-analysis [22-23]. We will use a significance level of 0.05, and apply 
the appropriate adjustments at the interim analysis to ensure that the overall type I error rate is 
maintained. We will also use the interim analysis to confirm that the effect size estimates are in line with 
the HESDE. 
 
We plan on a blinded early assessment of our assumption of equal variances in both study groups at 
approximately 25% accrual. No assessment of treatment differences will be made during this assessment, 
and a decrease in the total sample size will not be considered.   
 
Using articles identified by an unpublished systematic review of all antipsychotics measuring reduction in 
agitation at timepoints <24 hours (currently in development), we selected two randomized controlled 
trials comparing haloperidol vs placebo. Utilizing estimates from these articles, Wright et. al. (2001) and 
Breier et. al. (2002), for the effect of haloperidol at 2 hours against placebo (4.00 with a sample size of n 
= 126 and 4.60 with a sample size of n = 40, respectively), we arrive at a pooled mean estimate for M1 
(the assumed entire effect of the active control, haloperidol + lorazepam) of 4.14. We also combine the 
standard deviations of the differences between measurements at baseline and 2 hours from these two 
studies (5.00 and 5.90) to arrive at a pooled estimate of σ = 5.23, which we assume to be common to 
measurements of both of our treatment groups. If there is truly no difference between haloperidol + 
lorazepam and loxapine, then 140 total patients are required to be 90% sure that the upper limit of a one-
sided 95.2% confidence interval for the difference in the change in PANSS-EC scores between baseline 
and 2 hours in haloperidol + lorazepam and loxapine will be below the non-inferiority limit (M2) equal to 
2.61 (approximately 63% of the entire effect of the active control). We note that the margin M2 is chosen 
to maintain a clinically relevant non-inferiority margin.      
 
We will also plan an interim analysis at 50% accrual to test the non-inferiority limits, using the O'Brien 
and Fleming alpha spending limits to maintain an overall type I error rate of α = 0.05. This entails testing 
the non-inferiority limit with a 99.75% one-sided confidence interval at the first look, and a 95.2% one-
sided confidence interval after complete accrual.  
      


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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A priori stopping rules will be pre-specified with the project biostatistician in case that the interim 
analysis provides an estimate of futility. 
      
As per FDA guidance, this trial will demonstrate non-inferiority in both an intention-to-treat analysis 
(ITT) and an as-treated analysis. Although superiority trials generally utilize ITT analyses, this may 
reward sloppy planning or execution of the trial. If this occurs, non-inferiority would be demonstrated in 
an ITT analysis but would not be demonstrated in an as-treated analysis, and so is an important additional 
statistical test. 
 
Justification of a non-inferiority design 
The use of a non-inferiority design is appropriate in this trial for two reasons. First, we expect similar 
efficacy but better tolerability (i.e., side effects) with loxapine than with haloperidol + lorazepam. 
However, side effects and adverse events are relatively rare in both groups, and powering a standard 
superiority study on this basis would be unfeasible. Although it is considered theoretically possible that 
inhaled loxapine may be more efficacious than haloperidol + lorazepam at early timepoints (such as 5 & 
15 minutes), this has never been tested. Thus, powering a standard superiority trial is unfeasible. Second, 
utilizing a placebo as a sole comparison of the efficacy of loxapine is unethical in this trial. Thus, a study 
of loxapine is only ethical if it includes a standard of care active comparator (i.e, haloperidol + 
lorazepam). 
 
Secondary outcomes  
Measurement of efficacy at additional timepoints 
It is unknown how inhaled loxapine compares to IM haloperidol + lorazepam at early timepoints. One 
randomized study showed effects of inhaled loxapine 10mg as early as 10 minutes after administration 
(the earliest timepoint studied). Thus, a measure of particular interest is the reduction in agitation at 
timepoints other than the main outcome of the study (2 hours), particularly early timepoints such as 5 & 
15 minutes. After testing for normality, differences between drugs will be compared using an analysis of 
covariance (ANCOVA) with baseline score as the covariate. 
 
Measurement of side effects/adverse events 
The most important secondary outcome is the proportion of adverse events in each group. Serious adverse 
events such as death, a life-threatening condition, prolonged inpatient hospitalization, or disability will be 
reported to the sponsor and the FDA on the MedWatch 3500A form. These events are expected to be 
extremely rare. More common side effects such as dysgeusia or wheezing will be noted at each time 
point. In addition, the following will also be considered to be adverse events: pregnancy exposure, infant 
exposure during breast-feeding, overdose, abuse, misuse, medication errors, transmission of an infectious 
agent, or accidental pediatric exposure. The number of patients with adverse events will be compared 
between groups using chi-square. 
 
Measurement of length of stay 
Given the confounds inherent in disposition from the emergency department, lengths of stay will be 
measured instead with length of time to disposition order using a two-sample t-test. As lengths of stay are 
non-normally distributed, these will be log-transformed before analysis. 
 
Measurement of restraint use 
Although similar proportions of patients might be expected to be placed into restraints, rapid-acting 
calming medication such as loxapine would be expected to reduce the total patient time in restraints. The 
number of patients with any type of restraints (wrist, ankles, or other) will be compared using chi-square. 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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Date: 10/18/17 
Page 12 
 
The total time in restraints is likely to be normally distributed, and will be compared between groups 
using two-sample t-tests if the assumption of normality holds. 
 
Measurement of admissions vs discharge 
If clinicians are able to effectively engage with their patients, this might be expected to reduce admission 
rates. The number of admitted vs discharged patients will be compared between groups using chi-square. 
 
Time to administration of study medication 
It is likely that the time of administration (calculated as administration time – physician order time) will 
be reduced in patients who are using inhaled medications since these medications do not have to be drawn 
from a vial and injected. The difference in these times are expected to be normally distributed, and will be 
analyzed with two-sample t-tests if the assumption of normality holds. 
 
Measurement of additional medications 
Clinicians are of course free to treat their patient in any manner they deem appropriate. This may include 
adjunctive medications, although we will ask clinicians not to do so for the first 10 minutes. The number 
of patients receiving any additional medications will be compared between groups using chi-square. 
 
Ethical Considerations 
All patients will be consented before randomization and drug administration. Please see below for 
description of informed consent process: 
 
Figure 2: informed consent process 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
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Date: 10/18/17 
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This study will be conducted in accordance with all applicable government regulations and University of 
Arkansas for Medical Sciences research policies and procedures. This protocol and any amendments will 
be submitted and approved by the UAMS Institutional Review Board (IRB) to conduct the study.  
The formal consent of each subject, using the IRB-approved consent form, will be obtained before that 
subject is submitted to any study procedure. All subjects for this study will be provided a consent form 
describing this study and providing sufficient information in language suitable for subjects to make an 
informed decision about their participation in this study. The person obtaining consent will thoroughly 
explain each element of the document and outline the risks and benefits, alternate treatment(s), and 
requirements of the study. The consent process will take place as described in the “Study Population” 
section above, and subjects may take as much time as needed to make a decision about their participation.  
Participation privacy will be maintained and questions regarding participation will be answered. No 
coercion or undue influence will be used in the consent process. This consent form must be signed by the 
subject or legally authorized representative and the individual obtaining the consent. A copy of the signed 
consent will be given to the participant, and the informed consent process will be documented in each 
subject’s research record. 
 
Dissemination of Data 
Results of this study may be used for presentations, posters, or publications. The publications will not 
contain any identifiable information that could be linked to a participant.  
 
References 
Campillo A, Castillo E, Vilke GM, Hopper A, Ryan V, Wilson MP. First generation antipsychotics are 
still preferred in the emergency department but are often not administered with adjunctive medications. J 
Emerg Med. 2015; 49(6):901-906. 
 
Clinton JE, Sterner S, Stelmachers Z, Ruiz E. Haloperidol for the sedation of disruptive emergency 
patients. Ann Emerg Med. 1987; 16:319-322. 
 
De Berardis D, Fornaro M, Orsolini L, et al. The role of inhaled loxapine in the treatment of acute 
agitation in patients with psychiatric disorders: A clinical review. Int J Mol Sci. 2017; 18(349):1-15. 
 
Nordstrom K, Allen MH. Alternative delivery systems for agents to treat acute agitation: Progress to date. 
Drugs. 2013; 73:1783-1792. 
 
Raveendran NS. Rapid tranquilisation in psychiatric emergency settings in India: Pragmatic randomised 
controlled trial of intramuscular olanzapine versus intramuscular haloperidol plus promethazine. BMJ. 
2007; 335(7625):865. 
 
Wilson MP, Minassian A, Bahramzi M, Campillo A, Vilke GM. Despite expert recommendations, 
second-generation antipsychotics are not often prescribed in the emergency department. J Emerg Med. 
2014; 46(6):808-13. 
 


Title: A randomized double-blind multicenter double-dummy non-inferiority trial of inhaled loxapine and 
intramuscular haloperidol + lorazepam for the reduction of agitation 
PI: Wilson 
 
Version #: 11 
Date: 10/18/17 
Page 14 
 
Zeller SL, Holloman GH, Wilson MP. Management of agitation. Chapter in Section 10, “Emergency 
Psychiatry and Violence,” in Tasman A, Lieberman JA, Kay J, First MB, Riba MB [editors]. Psychiatry, 
4th edition. Oxford, UK: Wiley Publishing; 2014. 
 
 
Additional references may be found in: 
Zeller S, Nordstrom K, Wilson MP. The diagnosis and management of agitation. Cambridge Press. In 
press. 
https://www.amazon.com/Diagnosis-Management-Agitation-Scott-
Zeller/dp/110714812X/ref=sr_1_1?ie=UTF8&qid=1483904339&sr=8-1&keywords=zeller+wilson 
 
Appendices 
-REDCap forms for patient assessment 
-Consent/HIPAA forms 

ICF_001.pdf: 
Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 1 
 
University of Arkansas for Medical Sciences Informed Consent Form 
Why am I being asked to be in this research study? 
 Sometimes people become very excited in the emergency department, and speak with 
loud voices, move a lot, or even throw things. This is called agitation. 
 We want to learn more about how medications help people with certain kinds of agitation 
from schizophrenia or bipolar disorder. Although you are not agitated now, we are asking 
for permission to give you government-approved medications for agitation should you 
need treatment in the UAMS emergency department within the next 3 years. 
 This study will help us learn more about how people with agitation respond to certain 
medications and whether some medications work as well as others. 
 We are asking people like you with either schizophrenia or bipolar 1 disorder to help us. 
Approximately 140 people at two sites between 18 & 64 years of age will be part of this 
study. At least half of these participants, maybe more, will come from UAMS. 
 No matter which medications you receive – either haloperidol (also known as Haldol) + 
lorazepam (also known as Ativan) or loxapine (also known as Adasuve), these 
medications are government-approved for agitation.  
What if I don’t understand something? 
 This form may have words you don’t understand. Research staff will read it with you, if 
you like. 
 You may ask as many questions as you like before you decide whether you want to be in 
this study.   
 We are asking you to be in a research study. 
 You do not have to be in the study. 
 If you say yes, you can quit the study at any time. 
 Please take as much time as you need to make your choice. 
 You can still get your medical care from UAMS even if you are not in the study. 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 2 
 
 You are free to ask questions at any time before, during, or after you are in the study. 
 
What if I say yes, I want to be in this study? 
We first will see if you qualify to be in the study. We will: 
 Ask you some questions about yourself, including about your medical problems. 
 We will ask about your allergies. 
 We will ask if you mind being randomly assigned (like flipping a coin) to receive either 
of the study medications (haloperidol/lorazepam or inhaled loxapine) should you ever 
need them in the emergency department. 
 
If you qualify, we will do these things: 
 give you an electronic form with questions about your health and allergies. 
 read the questions out loud and fill out the form with you, if you like. 
 
If you are accepted into the study, we will do these things: 
 If you do not need treatment for agitation in the UAMS emergency department right now, 
then nothing will happen now, and nothing will happen unless you need that treatment. 
 If you are in the UAMS emergency department and your physician decides that you need 
treatment for agitation, you will receive both a medication that you breathe in (an inhaler) 
and an injection. Either the inhaler or the injection, but not both, will contain medication. 
We will not know in advance which group you will be in, and we cannot promise that 
you will receive one medication or the other. 
 For half of the people in the study, the injection will contain normal saline 
(a placebo, which has no medication, like salt water) but the inhaler will 
contain loxapine (also known as Adasuve). Loxapine is an inhaled 
medication that helps people calm down and think more clearly. You 
should not use loxapine if you have any allergy to medications called 
antipsychotics. You should also not use loxapine if you have asthma, 
COPD (a type of lung disease), if you are pregnant, if you are nursing an 
infant, or if you are over 64 years of age. 
 For the other half of the people in the study, the inhaler will contain 
nothing (a placebo) but the injection will contain 5 milligrams of 
haloperidol (also known as Haldol) and 2 milligrams of lorazepam (also 
known as Ativan).  


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 3 
 
Haloperidol is a type of medication which helps people calm down and 
think more clearly.  
 Lorazepam is a type of medication called a benzodiazepine. This 
medication helps people calm down and feel less anxious. You should not 
use either haloperidol or lorazepam if you have an allergy to 
antipsychotics or benzodiazepines, if you are pregnant,  
if you are nursing an infant, if you are over 64 years of age, if you have 
breathing difficulties, or if you have glaucoma.  
 
 Please note that your chance of being in either group is random “like a flip of a coin 
toss,” although we will not use a coin for this. Since your group assignment is unknown 
to the nurses or the doctors, they will also not know which group you will be in. If you 
somehow figure out what group you are in, we ask you not to tell the nurses or doctors so 
that they will not know either. If it ever becomes necessary for your doctor to know what 
drug regimen you were given, that information will be made available to him or her. 
 The total amount of time you will be observed in the emergency department is 
approximately 2.5-3 hours. We are going to check on you frequently no matter which 
medication you receive. You may have your vital signs taken and be asked how you feel 
from the medication afterwards, but you will not need to do anything else. You do not 
need to answer these questions if you don’t feel like it. 
 After you leave the emergency department, we will look in your medical chart for other 
things, including the total length of time you stayed in the emergency department, 
whether your doctor decided that you needed other medications for agitation, whether 
you have any other medical problems, whether you had any side effects from the 
medication, and whether you were admitted to the hospital or discharged home. 
How long will this study take?  
If you need treatment in the emergency department and are administered medication, the total 
length of time you will be observed is approximately 2.5-3 hours. 
Who will see the information about me that is collected? 
 The local study team will know your name and have access to your information.  
 We will do our best to make sure no one outside the study knows you are part of the 
study. 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 4 
 
 We will take your name off information that we collect from you during the study. 
 When we share the results of the study in medical journals, we will not include your 
name or any other information that allows people to identify you personally. 
 There are people who make sure the study is run the right way. These people may see 
information from the study about you including information that identifies you. They are: 
 The Emergency Medicine Foundation, who sponsored the research. 
 OHRP (Office for Human Research Protections), a federal agency 
 UAMS Institutional Review Board, which reviews all UAMS research 
 Other institutional oversight offices 
 Your study information will be sent to our research colleagues at Hennepin 
Medical Center in Minneapolis, but this information will include a code number 
instead of your name. 
 State law requires we tell the authorities if we learn 
 about possible child or adult abuse  
 that you might hurt yourself or someone else 
 
Where and how long will my information be kept?  
 We will code your information and keep the code in a locked file.  
 Only the researchers will have access to the code for your information. 
 We will store your information for 7 years 
 Your medical record will contain information that you received one of the drugs in the 
study.  
 We will put a copy of this form in your medical record. 
What if I say no, I do not want to be in this study? 
 Nothing bad will happen. You may still get one of these drugs if you are agitated in the 
emergency department, but we will not observe your reaction to this. We will not collect 
research information about how you responded to this medication. 
 You can still get medical care at UAMS.  
 
What happens if I say yes, but change my mind later? 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 5 
 
 If you are signing this form in clinic and not in the ER, it will be valid for 3 years, but if 
you come to the ER during that time and decide you don’t want to be in the study after all 
then you don’t have to join.  
 You can stop being in the study at any time, and you can ask us not to observe you when 
you are in the emergency department. 
 Nothing bad will happen. 
 You can still get medical care at UAMS. 
 If you decide to stop being in the study, call Dr Wilson at 501-686-5515 or send him a 
letter at the UAMS Department of Emergency Medicine, 4301 West Markham Street, slot 
#584, Little Rock, Arkansas, 72205. He will do everything possible to remove your 
information. However, this may be impossible in some cases if the data has already been 
reported. 
 
Can I be taken out of the study even if I want to continue? 
Yes, the study doctor (or head researcher) can take you out of the study if: 
 You do not follow study instructions. 
 It is not in your best interest to continue or if you bring a family member who objects to 
you being in the study. 
 The study is stopped for any reason. 
 The study drugs are unavailable, or if there is any other reason that we cannot administer 
you these medications and then observe you. 
 
If I stop being in the study, what will happen to any information collected from me in the 
study? 
 We may be able to remove your information if it has not already been reported or sent, 
without identifiers, to a central site. We will not be able to remove you if we have already 
shared your information. 
 
Will my information from the study be used for anything else, including future research? 
 No. Your information will be used only in this study. 
 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 6 
 
Will it cost me anything to be in the study? 
 
The study drugs haloperidol + lorazepam or inhaled loxapine will be provided to you free of 
charge. You and/or your insurance company will be billed for your regular medical care in the 
usual manner for your disease.  
Will I be paid? 
No. You will not be paid for being in this study. 
 
Will being in this study help me in any way? 
Being in the study may help you because you will get treatment for your agitation, although it 
may not help you more than if you got similar treatment for your agitation outside of this study. 
We think that being in the study will help people with agitation in the future. What we learn may 
help in the following ways:  
 We may learn how individuals with agitation respond to the study medications. 
 
What are the risks of being in this study? 
The risks are: 
 Someone could find out that you were in the study and learn something about you that 
you did not want others to know. We will do our best to protect your privacy. 
 The questions could make you sad or upset.  
 You may be allergic or have a bad reaction to the study drugs. Although these drugs have 
been approved by the United States government agency called the Food & Drug 
Administration (or FDA), you may have a different reaction to them. In the case of 
loxapine, these risks could include hypersensitivity (serious skin reactions), wheezing or 
difficulty breathing, increased chance of death or stroke if you are over 65, low blood 
pressure, passing out, seizures, impairment of thinking or motor skills, or urinary 
retention. Please note that these risks would be the same if you use loxapine outside of 
this study. In the case of haloperidol & lorazepam, these risks could include increased 
chance of death if you are over 65, QT prolongation (a type of heart rhythm disturbance), 
increased motor movements or abnormal contractions of muscles, increased chance of 
pneumonia, impairment of thinking or motor skills, possible disturbance of white blood 
cells (the cells in your body that fight off infection, also termed leukopenia/neutropenia),  


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 7 
 
fast heart rate, worsening of glaucoma (if you have this disease), and low blood pressure 
or high blood pressure.  
 In addition, this study may involve other risks that are not currently known to you or your 
embryo or fetus if you are pregnant. Please let us know whether you are pregnant before 
you get any study drugs. 
What if I get sick or hurt while I’m in this study?  
 If you get hurt when you are here for the study, we will help you get the care you need. 
This may include first aid, emergency care and/or follow-up care. 
 If you are not here and get hurt or sick, and think it is because of the study, do these 
things: 
 tell your doctor or ER staff  
o the name of this study (say “the Adasuve study”) 
o the name of the head researcher for this study (Dr Wilson) 
o a copy of this form if you have it 
 This treatment may be billed to you or your insurance company in the normal manner. 
Normally, no other form of payment is available. 
 You will not give up any of your legal rights by signing this form. 
 
What are the alternatives to being in this study?  
You do not have to be in this study. If you do not want to be in this study, your options are: 
 To not be in the study. In this case, you may still receive these medications. However, we 
will not observe your response to them, and we will not collect information about you. 
What if new information comes up about the study? 
 We want you to know about anything that may change your mind about being in the 
study.  
 The researcher will let you know by: 
 telling you in the emergency department 
 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 8 
 
Where can I find more information about this clinical trial?  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. law. This website will not include information that can identify you. At most, the 
website will include a summary of the results. You can search this website any time. 
What if I have questions? 
 Please call the head researcher of the study, Dr Wilson at 501-686-8729, if you: 
 have any questions about this study 
 have questions about your rights 
 feel you have been injured in any way by being in this study 
 You can also call the office that supervises research (UAMS Institutional Review Board) 
at 501-686-5667 if you 
 have questions about this study 
 have questions about your rights 
 can’t reach the study team 
 need to speak to someone not directly involved with this study 
What should I do if I want to be in the study? 
Sign this form. We will give you a copy of this form to keep. 
 
By signing the document, I am saying: 
 I understand that joining this study is voluntary. 
 I agree to be in the study. 
 Someone talked with me about the information in this document and answered all my 
questions.  
 
I know that: 
 I can stop all parts of the study at any time and nothing bad will happen to me. 


Study Title: A randomized double-blind multicenter double-dummy non-inferiority trial of 
inhaled loxapine and intramuscular haloperidol + intramuscular lorazepam 
PI (researcher): 
Michael Wilson 
Institution: 
University of Arkansas for Medical Sciences 
Sponsor: 
Emergency Medicine Foundation 
Version #: 9 
 
IRB# 206292 
Date: 
09/26/17 
Page 9 
 
 I can call the office that supervises research (UAMS Institutional Review Board) at 501-
686-5667 if I have any questions about the study or about my rights. 
 My decision will not change my medical care at UAMS. 
 
 
I agree to be part of this study: 
 
 
____________________________  
 
____________________________ 
Your name (please print) 
 
 
 
Your signature 
 
 
___________________________ 
Date 
 
 
_____________________________  
 
______________________________ 
Name of legally responsible person (please print) 
Signature of legally responsible person 
 
Relationship to you: ________________________________________________________ 
 
 
 
__________________________________  
_______________________________ 
Name of person obtaining consent (please print)  
Signature of person obtaining consent 
 
____________________________ 
Date