Enhancing Adherence and Outcomes in Bipolar Disorder With Abilify Maintena + a Targeted Behavioral Approach to Promote Sustained Adherence and Behavioral Change
Phase: PHASE4
Conditions: Bipolar Disorder, Medication Adherence, Medication Non Adherence
Sponsor: Martha Sajatovic

 
1 
Title: Enhancing adherence and outcomes in bipolar disorder with Abilify Maintena + a targeted 
behavioral approach to promote sustained adherence and behavioral change 
 
Principal Investigator: Martha Sajatovic MD 
Co-Investigators: Jennifer Levin PhD, Sarah Lytle MD, Luis Ramirez MD, Curtis Tatsuoka PhD 
 
Version Date:  December 18, 2017 
 
Background: 
Poor adherence with medication in bipolar disorder (BD) is associated with relapse, high use of health 
resources, poor outcomes, and suicide. The proposed project will build upon the recent availability of long-acting 
aripiprazole (Abilify Maintena) combined with manualized adherence support to meet the specific needs of poorly 
adherent BD patients. An innovative and clinically important “deliverable” of the proposal will be a practical 
treatment approach that can be scaled-up widely in routine practice settings. 
 
Long-acting injectable antipsychotic (LAI) in BD: Oral Abilify (aripiprazole) is effective in the treatment of 
patients with BD when prescribed as an acute anti-manic agent and for the maintenance treatment of bipolar 
disorder.  Abilify Maintena is an intramuscular (IM) depot formulation of oral aripiprazole (Abilify). It is a sterile 
lyophilized powder that, when reconstituted with sterile water for injection, forms an injectable suspension that 
can be administered monthly. After an initial injection of Abilify Maintena, along with an overlapping 14-day 
dosing of oral antipsychotic treatment, subsequent injections of Abilify Maintena provide uninterrupted 
medication coverage for 30 days at a time. Abilify Maintena appears to be as effective as standard oral Abilify 
and may maximize patient adherence. Recent clinical trials suggest that Abilify Maintena is effective for the 
treatment of patients with BD. 
 
Customized Adherence Enhancement (CAE) is a brief behavioral intervention that improves adherence 
approximately 30% more than an educational control in adults with BD. The CAE program is a brief, 
practical intervention consisting of a series of up to four psychosocial treatment modules based upon an adult’s 
unique adherence barriers: 1) Psychoeducation on BD Medications; 2) Communication with Providers; 3) 
Strategies to Enhance Medication Routines; and 4) Targeting Substance Use Problems with Modified 
Motivational Enhancement Therapy. These CAE modules are derived from existing evidence-based approaches 
for patients with BD (Bauer 2004, Bauer 2006a, Bauer 2006b, Frank 2005, Sajatovic 2005, Ziedonis 2005). Each 
CAE module can be combined with other CAE modules. The material can be delivered in approximately 6 in-
person sessions.  
 
These investigators conducted 2 pilot trials of CAE that were nearly identical in design. The first trial was an 
NIMH-funded 6-month pilot evaluating the feasibility/acceptability and preliminary efficacy of CAE in 43 poorly 
adherent BD adults (Sajatovic 2012a) and the second trial was an industry-funded 3-month trial in 43 poorly 
adherent BD adults(Sajatovic 2012b). In both trials, the primary outcome was adherence evaluated with the 
Tablet Routines Questionnaire (TRQ; Peet 1991, Scott 2002). Pooled results indicated mean baseline non-
adherence (proportion of missed medication) was 40.2% (SD 31.6%) within the past week and 42.8% (SD 
28.1%) missed medication within the past month. At 3 months, mean missed medication decreased to 18.5% 
(SD 31.9) for the past week, and 15.8% (SD 26.1%) for the past month. At 6-month follow-up, mean missed 
tablets was 25.2% (SD 36.2%) for the past week and 21.3% (SD 29.1%) for the past month.  
 
A 6-month, prospective, randomized controlled trial (RCT) of CAE vs. an educational control is being conducted 
in 184 poorly adherent adults with BD. To enhance generalizability, CAE is delivered by social workers. Interim 
RCT outcomes (CAE N=24, EDU N=26) show that CAE is associated with improved adherence as measured by 
the Tablet Routines Questionnaire (TRQ mean change=46.0, SD=38.7) compared to an educational control 
(EDU) (TRQ mean change=17.3, SD=40.3, p=.017). Six-month MEMS adherence change was also greater with 
CAE (mean change 45.7, SD 40.6) compared to EDU (mean change 15.9 (SD 39.9), p=.015. Effect sizes for 
CAE in both TRQ and MEMS are approximately 0.75, comparing favorably with effect size for response to BD 
medications. 
 
 

 
2 
Combining LAI + CAE dramatically improves adherence, symptoms and functional outcomes in people 
with schizophrenia and schizoaffective disorder: These investigators tested a combined LAI + CAE approach 
(CAE-L) in 2 preliminary studies. CAE-L Study 1 (Sajatovic 2013) enrolled 30 homeless or recently homeless 
individuals with schizoaffective or schizophrenia.  The LAI used was haloperidol decanoate. Primary outcomes 
were TRQ and housing status.  Secondary outcomes included psychiatric symptoms and functional status.  Mean 
sample age was 41.8 years with a high proportion of minorities and single/never married individuals. CAE-L was 
associated with substantial improvement in concomitant orally prescribed medication, which changed from 
missing 46% of prescribed medication at study enrollment to only 10% of prescribed medication at study end. 
Mean proportion of time in sub-optimal housing went from 56% in the 6 months prior to study enrollment to 41 
% in the first 3 months of the study and 14% in the last 3 months of the study.  There were also significant 
improvements in psychiatric symptoms and functional status.   
 
In CAE-L Study 2 (Sajatovic 2016), CAE-L was delivered by social workers and used the LAI paliperidone 
palmitate. This 6-month prospective, uncontrolled trial of CAE-L in 30 recently homeless individuals with 
schizophrenia or schizoaffective disorder assessed medication adherence using the TRQ and injection 
frequency.  Psychiatric symptoms were measured with the Positive and Negative Syndrome Scale (PANSS), 
Brief Psychiatric Rating Scale (BPRS) and global psychopathology. Standardized measures of extrapyramidal 
symptoms included the Simpson Angus Scale (SAS), the Barnes Akathisia Scale BAS), and the Extrapyramidal 
Symptoms Scale-Abbreviated version (ESRS). Social functioning was assessed via the Social and Occupational 
Functioning Assessment Scale (SOFAS).  Mean age of the sample was 43.6 years, mainly minorities, 
single/never married with a mean of 11.55 years of education.  Baseline rate of substance abuse within the past 
year was 40.0%. Four individuals (13.3%) terminated the study prematurely. CAE + LAI was associated with 
improved adherence as measured by the TRQ (p=.02). There were significant improvements in PANSS (p <.01), 
BPRS (p<.001), CGI (p =.003) and SOFAS (p=.005).  There were no significant mean changes on SAS, BAS, 
ESRS-A.  The CAE-L studies combined dataset (Table 1)(Sajatovic M 2016) shows changes in medication 
adherence, psychiatric symptoms, global psychopathology and social functioning. Adherence with regular LAI 
injections was excellent, with > 90% receiving injections within 1 week of regularly scheduled treatment.  
 
Table 1: Combined data of CAE-L for 60 poorly adherent patients with schizoaffective disorder/schizophrenia 
Variable 
Screen 
Baseline 
Wk 13 
Wk 25 
N 
Statistic 
TRQ Mean   
 Past Week 
 Past Month 
 
50.4% (32.4) 
45.2% (33.6) 
 
26.7% (29.3) 
32.5% (30.4) 
 
16.8% (29.5) 
16.2% (24.9) 
 
17.1% (30.6) 
13.8% (23.2) 
 
26 
25 
 
.001 
.002 
Injection Frequency 
- 
- 
86.1 (32.8) 
90.5 (30.1) 
50 
.060 
BPRS Mean  
- 
44.1 (8.3) 
33.9 (7.9) 
30.8 (8.3) 
41 
< .001 
PANSS Mean  
 Positive Symptoms Scale    
 Negative Symptoms Scale 
 Composite Scale (Pos - Neg)  
 General Psychopathology Scale 
 
- 
- 
- 
- 
 
16.7 (6.3) 
28.5 (10.9) 
14.9 (10.3) 
19.9 (18.9) 
 
- 
- 
- 
- 
 
12.4 (5.8) 
20.8 (7.9) 
7.8 (8.2) 
9.8 (14.1) 
 
36 
35 
36 
36 
 
.001 
<.001 
<.001 
<.001 
CGI  Severity Mean  
- 
4.6 (0.9) 
3.4 (0.7) 
3.1 (0.8) 
38 
<.001 
SOFAS Mean  
- 
51.1 (8.1) 
- 
61.3 (9.7) 
40 
<.001 
 
In summary, LAI can maximize medication adherence, while CAE addresses individual barriers to 
sustained adherence and behavioral change. Combining LAI + CAE improves adherence, symptoms and 
functioning in high-risk people with primary psychotic disorders. The proposed project will test the 
efficacy of combining Abilify Maintena with CAE to help improve outcomes in poorly adherent patients 
with BD.  Pilot data suggest that adherence with concomitantly prescribed psychotropic drugs improves 
with LAI + CAE. The findings have particular relevance to BD because many BD patients are on 
concomitant oral psychotropic drugs in addition to antipsychotic. Thus, it is expected that combining 
CAE with LAI will lead to a “halo effect” in that these BD patients will engage in their own care more 
broadly. 
 

 
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Methods: 
Rationale for combined drug + behavioral 
approach: In spite of the advantages of LAI in 
promoting adherence and treating BD symptoms, 
simply switching individuals who are poorly adherence 
to LAI is often not enough to sustain long-term 
behavioral change. Additionally, many people with BD 
are on multiple psychotropic medications, some of 
which are not available in LAI formulations. Adherence 
is a multi-component process that involves having 1) 
knowledge of what is needed to manage a medical 
condition, 2) organizational resources to put a self-
management 
plan 
into 
action, 
3) 
ability 
to 
communicate with health care professionals to 
effectively manage a care plan, and 4) understanding 
of the impact of substance use on adherence. 
Problems with any of these components can impede adherence, and when multiple barriers are present, 
adherence is particularly difficult. Each additional barrier increases the likelihood of poor adherence by 30% 
(Zeber 2011). While addressing adherence barriers is challenging, the gains in outcomes may be substantial 
and improved adherence behavior is associated with reduced psychiatric symptom burden and improved 
functioning(Levin 2014, Sajatovic 2013, Sajatovic 2012a, Sajatovic 2012b).  
 
An important limitation of the CAE-L pilots is that they excluded individuals with BD. The pilot studies 
combined LAI + CAE data suggested that patients with schizoaffective disorder (N=44) did just as well 
as those with schizophrenia (N=16) with respect to adherence, symptom and functional outcomes (Levin 
et al., 2017). Combining Maintena with a practical method of adherence support has potential to enhance 
uptake and optimize enduring adherence to medication in patients with BD. 
 
Project Design: 
Overview: 6-month, prospective, trial testing the effects of Maintena augmented with CAE in 30 poorly 
adherence patients with BD.  After a 2-month study start-up period, patients will be enrolled over a 16 month 
enrollment period (months 2-18). The targeted enrollment of approximately 2 participants/month is reasonable 
given previous recruitment with the CAE + LAI pilots.  Primary outcomes will be change from baseline in 
adherence as identified by the Tablet Routines Questionnaire (TRQ) and injection frequency at the 6-month time-
point. We will also evaluate changes in secondary outcomes, including BD symptoms (BPRS), depressive and 
global psychopathology symptoms, functional status, and adherence attitudes. Additional exploratory assessments 
will include health resource use, adherence barriers, substance use and neurocognition. Outcome measures will 
be assessed at Screening, Baseline, and Weeks 4- 24 as noted in Table 2/Study Schedule of Events.  Because 
the study design will be nearly identical to the 2 previously conducted CAE + LAI pilots, it will be possible to 
compare primary and secondary outcomes of this study of individuals with BD to individuals with 
schizophrenia/schizoaffective disorder. The study will be operationalized in 4 specific Aims: 
 
Aim 1: Test whether combined Maintena + CAE (Maintena +) is associated with improved treatment adherence 
Hypothesis 1: At 6-month follow-up, poorly adherent BD patients receiving Maintena + will have significant 
improvement in medication adherence as measured by the TRQ.  
Hypothesis 2: At 6-month follow-up we also expect that mean LAI adherence as measured by injection frequency 
will meet or exceed 80%.  The 80% threshold is widely viewed in the treatment adherence literature as an 
“acceptable” degree of adherence. 
 
Aim 2: Test whether Maintena + is associated with reduction in BD symptoms, improved functioning and better 
treatment attitudes  
Hypothesis 3: Maintena + will be associated with significant reduction in symptoms, improved functioning and better 
treatment attitudes.  
 
Figure 1. Targeted mechanism of action of a customized 
adherence enhancement approach (CAE-L) in BD  
Adherence 
 
Maintena 
+ CAE  
BD 
Symptoms 
Function 
 
Medication 
Attitudes 
Adherence Barriers 
• BD Knowledge 
• Medication Routines 
• Communication with Clinicians 
• Substance use   

 
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Aim 3: Compare how individuals with BD participating in a care approach that combines LAI with a brief behavioral 
approach that targets adherence enhancement respond on adherence, symptom and functional outcomes in 
comparison to individuals with schizophrenia/schizoaffective disorder.  This comparison will use outcomes from 
the current study vs. historical data from recently conducted trials in schizophrenia/schizoaffective disorder. 
Corresponding effect sizes will be computed.  Based on past data comparing individuals with schizophrenia vs. 
those with schizoaffective disorder, we expect that BD patients will do at least as well, and possibly better than 
individuals with primary psychotic disorders.  
 
Aim 4: Investigate whether improved adherence behaviors will be associated with reductions in treatment 
adherence barriers. 
We expect that improved BD knowledge, communication with clinicians, medication routines and reduction in 
substance use will all be associated with improved adherence. Exploratory analysis will investigate mechanistic 
effect of Maintena + by evaluating whether change in BD knowledge, communication with clinicians, medication 
routines and substance use is related to adherence change. Additional exploratory measures will evaluate health 
resource use, substance use/abuse and neurocognition.  
 
Study Population:   
The study will enroll 30 individuals age 18 and over with Type 1 or Type 2 BD. Patients will be recruited from 
inpatient, ambulatory services and from the community by a variety of methods: 
1. Study staff will inform the University Hospitals of Cleveland Medical Center (UHCMC) clinical psychiatry 
providers about the study.  
2. Study staff will also present information about the study to the staff at local Community Mental Health Clinics 
(CMHCs) and other organizations serving persons with mental illness. After presenting the study in these 
group and individual settings, the study staff will maintain regular contact with staff at these organizations to 
inquire about new referrals.  
3. IRB-approved recruitment fliers will be posted and distributed with permission of staff at CMHCs and other 
organizations serving persons with mental illness.  
4. Recruitment will be done by oral request to patients coming for regularly scheduled clinic visits at UHCMC 
or area CMHCs. Requests for participation may be initiated by a clinic staff member, by a research associate 
on site, or in some cases may be initiated by patients themselves.  
5. Patients with BD will be identified from the UHCMC electronic medical record and using an IRB-approved 
process, be invited to participate in study screening. 
6. Patients may also be recruited under the MHERP/NBOC Prescreen protocol. 
All individuals with BD who are referred will be considered for possible inclusion in the study. A Screening Form 
for each patient will be completed regardless of whether the patient is ultimately enrolled. The form will detail 
reasons for exclusion, allowing an estimate of sample generalizability. Patients recruited in response to an IRB-
approved recruitment method may be prescreened under the IRB-approved protocol, “Prescreening and 
Recruitment for the Mental Health Effectiveness Research Program and Neurological and Behavioral Outcomes 
Center” (MHERP/NBOC Prescreen) [IRB # 03-10-09].  
 
The study PI (Dr. Sajatovic, Professor of Psychiatry at CWRU and UHCMC) will oversee and be responsible for 
all aspects of the study including study regulatory matters, human subjects requirements, study implementation, 
study staff supervision, and data collection, analysis and reporting.  Study Co-investigators will assist the study 
PI in study referral, clinical and safety monitoring, training and oversight of interventionists, and participant 
retention. The PI has successfully conducted multiple treatment adherence studies over the last decade and has 
an extensive track-record of robust recruitment of non-adherent patients with BD and other serious mental 
illnesses. Diagnosis will be confirmed with a standardized brief interview commonly utilized in clinical trials, the 
Mini International Neuropsychiatric Inventory (MINI).  In order to facilitate a relative comparison of BD patient 
response to outcomes in this study vs. recently completed pilot trials, we will deliberately recruit individuals with 
similar study entry level symptom severity. In the proposal trial, study entry Brief Psychiatric Symptom Rating 
Scale (BPRS) scores will not be below 1 standard deviation of the mean BPRS in pilot work. 
 
Inclusion Criteria: 
1. Individuals age 18 and older with BD Type 1 or 2 as confirmed by the Mini International Psychiatric 
Inventory (MINI).  

 
5 
2. Known to have medication treatment adherence problems as identified by the Treatment Routines 
Questionnaire  (TRQ, 20% or more missed medications in past week or past month) 
3. Screening BPRS score of ≥ 36 
4. Ability to be rated on psychiatric rating scales. 
5. Willingness to take LAI 
6. Currently in treatment or scheduled to receive treatment at a Community Mental Health Clinic (CMHC) 
or other clinical setting able to provide mental health care during and after study participation 
7. Able to provide written, informed consent to study participation. 
 
Exclusion Criteria: 
1. Individuals on LAI immediately prior to study enrollment. 
2. Individuals with known intolerance or resistance to either oral aripiprazole or LAI formulation of 
aripiprazole 
3. Prior or current treatment with clozapine 
4. Medical condition or illness, which in the opinion of the research psychiatrist, would interfere with the 
patient’s ability to participate in the trial 
5. Physical dependence on substances (alcohol or illicit drugs) likely to lead to withdrawal reaction during 
the course of the study in the clinical opinion of the treated research psychiatrist 
6. Immediate risk of harm to self or others 
7. Female who is currently pregnant or breastfeeding 
 
Study Medication: Medication dosing will follow recommendations in the Maintena package insert. For patients 
who have never received aripiprazole, there will be a brief oral tolerance testing (OTT) of up to 14 days. 
Individuals who tolerate OTT will then receive 400 mg of Maintena administered IM in the gluteal or deltoid 
location, and oral Abilify will continue for an additional 14 days, after which oral medication will be discontinued. 
After the initial IM injection, individuals will continue to receive injections of Maintena every month for a total of 6 
months.  The standard dosage of 400 mg IM will be administered in this maintenance treatment phase although 
clinicians may administer a lower dosage of 300 mg IM depending on clinical response. 
 
Concomitant Medications As it is known that multi-drug maintenance treatment is the rule rather than the 
exception in BD, and in order to increase generalizability of study findings, patients will be permitted to continue 
other psychotropic maintenance treatments. Maintenance treatments are defined as traditional mood stabilizing 
drugs (such as lithium, valproate or lamotrigine), or antidepressants that have been continued for at least one 
month at a stable dosage.  Dosing on other concomitant treatments is required to remain unchanged for the 
duration of the study. Medications for side effects (for example, benztropine) may be given at the discretion of 
the treating psychiatrist. Hypnotic drugs for insomnia/sleep that have been prescribed for at least 30 days may 
continue to be administered daily (for example zolpidem) at the same dosage. 
 
CAE: The CAE intervention will be modeled and delivered using procedures used in the CAE + LAI pilots. CAE 
will be delivered by a trained social worker to optimize generalizability.  CAE session will be delivered on the 
same day (either immediately before or immediately after Maintena injection). Supervision will be conducted with 
a PhD psychologist who helped develop CAE and training will be reinforced as needed. 
 
Measures and Schedule of Events: Table 2 shows the assessment measures, timeline the measures are 
given, and other specific procedures in the study. Demographic and clinical variables measured at baseline will 
include age, gender, race/ethnicity, living situation, cumulative medical burden and socioeconomic status at 
baseline. As in 2 previous successful studies using the medication + adherence support approach in high-risk 
SMI (Sajatovic 2012a, Sajatovic 2012b) the primary outcome measure will be adherence as assessed via the 
Tablet Routines Questionnaire (TRQ) 
 
Adherence: A number of investigators have defined “good” adherence in serious mental illness as missing no 
more than 20% of medication (Gilmer 2004, Valenstein 2004). In previous studies, we demonstrated that this 
cut-off is sufficient to detect adherence change over time with CAE (Levin 2014, Velligan 2010).  Adherence to 
Maintena will be assessed using the same injection frequency benchmarks used in the previous CAE-L studies 
(injection is counted as “adherent” if administered within 7 days of when it is scheduled to be administered).  

 
6 
Barriers assessed include BD knowledge, communication with clinicians, medication routines, and substance 
use.  
 
Other measures: 
Symptoms: Symptoms of BD will be addressed using the Brief Psychiatric Rating Scale (BPRS) developed by 
Overall and colleagues (Overall 1962), the Young Mania Rating Scale (Young 1978) and the Montgomery Asberg 
Rating Scale (Montgomery 1979), Global psychopathology will be measured with the Clinical Global Impressions  
, a widely used scale which evaluates illness severity on a 1 to 7 point continuum. Severity of illness ratings on 
the CGI have reported reliability scores ranging from 0.41-0.66. 
 
Functioning: Life and Work Functional status will be evaluated using the Social and Occupational Functioning 
Scale (Morosini 2000) and the GAF. The GAF is a 100-point single-item scale which measures global functioning 
of psychiatric patients and is widely utilized in clinical studies involving Seriously Mentally Ill patients (Jones 
1995).   
  
Adherence Attitudes:   
The Drug Attitude Inventory () is used to measure attitudes towards medication among individuals with serious 
mental illness (Awad 1993), and is known to be relatively unaffected by psychiatric symptom severity (Sajatovic 
2002). The DAI was originally developed to assess the attitudes and subjective experience of patients with 
schizophrenia being treated with antipsychotic medications and has also been widely utilized with other seriously 
mentally ill populations receiving psychotropic medication (Sajatovic 2003). The 10-item version of the scale will 
be utilized (Awad 1993).  
 
Attitude towards Medication Questionnaire (AMSQ): A modification of the Lithium Attitudes Questionnaire, the 
AMSQ evaluates an individual’s attitudes towards psychiatric medication.  The AMSQ comprises 19 items 
grouped into 7 subscales: general opposition to prophylaxis (4 items), denial of therapeutic effectiveness (2 
items), fear of side effects (2 items), difficulty with medication routines (4 items), denial of illness severity (3 
items), negative attitudes toward drugs in general (3 items), and lack of information about psychiatric medication 
(1 item).  Higher scores on each subscale represent more negative attitudes toward mood stabilizers.  
 
Adherence Barriers:  
BD Knowledge: Oxford Bipolar Knowledge Questionnaires 40-item self-report questionnaire used to assess 
knowledge of BD management on a 3-point Likert scale from agree to disagree (Bilderbeck 2016). 
 
Medication Routines: Routines will be assessed using The Self-Report Habit Index (SRHI), a 12-item self-report 
measure of habit strength and will be administered regarding the habit of taking medication (Verplanken 2003). 
 
Communication with Providers: Provider communication will be assessed the Communication Styles Scale, a 
patient rated measure of the impact of physician communication style on medication beliefs and adherence 
behavior in depressed patients(Bultman 2000). 
 
Motivation to Reduce Substance Use: Motivation to reduce the use of substances will be assessed using the 19 
item Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES 8A) (Miller WR 1996).   
 
Neurocognition:  Trail Making Test Parts A and B (Howieson 2004) and Animal Fluency Test (Lezak 2012) will 
be administered to assess for executive functioning and semantic verbal fluency, respectively.  
 
Health Resource Use: Resources that are typically utilized by the most severely ill individuals with BD include 
emergency care and hospitalization.  Resource use in the 6-month period prior to study enrollment and in the 6-
month study period will be evaluated. 
  
Alcohol and Substance Use: Alcohol use will be evaluated using The Alcohol Use Disorders Identification Test  
– Self-Report Version (AUDIT), a 10-item measure used to screen for excessive alcohol use developed by the 
World Health Organization (WHO)(Babor 2001, Saunders 1993). Drug use will be evaluated using the Drug 

 
7 
Abuse Screening Test (DAST-10), a 10-item abbreviated version of the original 28-item DAST created to assess 
drug-related problems in the past year (Babor 2001, Maisto 2000).  
 
Satisfaction with treatment:  Treatment acceptability and satisfaction will be assessed with a Likert Scale. 
 
Safety Evaluations:   
Safety evaluations will include baseline and Week 24/End-of-study basic laboratory evaluations (comprehensive 
metabolic panel, lipid profile, CBC with differential) and pregnancy testing for women.  EKG will be conducted at 
baseline, week 4 and Week 24/End-of-study.  Patient vital signs and weight will be collected at each study visit 
(baseline/V1, V2, V3, V4, V5, V6, V7, V8).  Standardized measures of involuntary movements/ extrapyramidal 
symptoms will be assessed with the Simpson Angus Scale (SAS), the Barnes Akathisia Scale (BAS), the 
Abnormal Involuntary Movement Scale (AIMS) and the Extrapyramidal Symptoms Scale-Abbreviated version 
(ESRS-A). Finally, reported side effects will also be evaluated at each study visit using a form derived from the 
previous CAE-L studies. 
Table 2: Measures and Study Schedule of Events 
Visit 
Screen 
BL/ 
V1 
V2 
V3 
V4  
V5 
V6 
V7  
Timing┼ 
−14 d to −1d 
0 W 
4W  
8W  
12W  
16W 
20W  
24W  
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
Adherence Behavior:  
TRQ 
LAI Injection Frequency* 
X 
X 
X 
X 
X 
X 
X 
X 
Non-psychotropic drug TRQ 
X 
 
 
 
X 
 
 
X 
MINI 
X 
 
 
 
 
 
 
 
CAE module allocation and 
assessment of 
Adherence barriers  
X 
 
 
 
 
 
 
X 
Physician Exam and interview 
X 
 
 
 
 
 
 
X 
Demographics, medical burden 
X 
 
 
 
 
 
 
 
Laboratory testing 
X 
 
 
 
X 
 
 
X 
EKG 
X 
 
X 
 
 
 
 
X 
Adherence Attitudes: DAI, AMSQ 
 
X 
 
 
X 
 
 
X 
Symptoms: BPRS, YMRS, MADRS, 
CGI 
X† 
X 
 
 
X 
 
 
X 
Functioning: SOFAS, GAF 
 
X 
 
 
 
 
 
X 
Health resource use  
 
X 
 
 
 
 
 
X 
Alcohol/Substance Use:   
AUDIT, DAST-10 
 
X 
 
 
X 
 
 
X 
Trails A & B, Animal Fluency 
X 
 
 
 
 
 
 
X 
Weight and vitals 
 
X 
X 
X 
X 
X 
X 
X 
Reported Side Effects 
 
X 
X 
X 
X 
X 
X 
X 
Extrapyramidal symptoms:   
AIMS**, SAS, BAS, ESRS-A 
X 
X 
X 
X 
X 
X 
X 
X 
Patient Satisfaction  
 
 
 
 
X 
 
 
X 
Research Clinician assessment  
 
X 
X 
X 
X 
X 
X 
X 
CAE sessions 
 
X 
X 
X 
X 
X 
X 
X 
Oral aripiprazole Dispensing*** 
X 
X 
 
 
 
 
 
 
LAI Injection 
 
X 
X 
X 
X 
X 
X 
X 
┼Timing of visits is approximate. 
* LAI Injection frequency will be calculated at weeks 12 & 24. 
** AIMS will only be administered at BL and W24/Term 
*** Dispensing of oral medication is patient specific and may include a 14-day oral tolerability test prior to first LAI injection, or 
dispensing of anti-side effect medications. 
† BRPS will be the only symptom evaluated at screen 
Laboratory testing includes: Comprehensive metabolic panel, CBC with differential, Thyroid function.  Pre-menopausal females will 
require serum pregnancy testing.  Women of childbearing potential must be using medically accepted methods of birth control.  Week 
12 lab testing will only include serum pregnancy testing for pre-menopausal females. Pregnancy testing may also be done at any time 
point if a woman feels she may be pregnant.  
 
 
 

 
8 
Serious Adverse Event Reporting 
1. Serious adverse events (SAEs) and other safety information will be collected and reported to the relevant 
government authority in accordance with the current Code of Federal Regulations 
2. Safety Information is defined as, any information from any source containing information such as: 
 
Adverse event or suspicion thereof 
 
Lack of efficacy 
 
Overdose/incorrect dosage (accidental or intentional) 
 
Abuse/misuse (e.g., patients sharing medication) even without resulting adverse reaction 
 
Accidental exposure (e.g., child takes parent’s medication) 
 
Medication error 
 
Withdrawal reactions 
 
Disease progression/exacerbation of existing disease 
 
Drug-drug/Drug-food interaction 
 
Reports of unexpected benefit 
 
Exposure to drug during pregnancy, where the embryo or fetus may have been exposed to medicinal 
products (either through maternal exposure or transmission of a medicinal product via semen following 
paternal exposure). 
 
Exposure to drug during lactation (including uneventful) 
 
Suspected counterfeit product 
 
Suspected transfer of infectious disease/agent by the medicinal product concerned. 
 
Product complaint report (any deficiencies related to the identity, quality, labeling, durability, reliability, 
efficacy, performance of a medicinal product, suspected counterfeit product) 
 
Pediatric use (if not an approved use) 
 
Occupational exposure 
 
Off-label use (if not part of the study design) 
3. SAEs and safety information will be collected from first use of an Otsuka product until 28 days after 
discontinuation.  
 
Data Management & Analyses: Study data will be collected and managed using REDCap(Harris 2009), a 
secure, web-based application designed to support data capture for research studies.  
 
Sample Size and Power: We propose to enroll 30 individuals with BD who receive Maintena +. Based on our 
prior studies (Sajatovic 2012a, Sajatovic 2012b), we conservatively assume 20% of participants will discontinue 
study participation during the 24 week study period and that the effect size of CAE-L will be similar to that of 
CAE-L in prior studies (effect size d=.60). Type I error level of 0.05 will be adopted for all tests. 
The primary outcomes measure will be change in adherence behavior and the mean LAI injection frequency 
at 6-months. Adherence rates will be calculated for TRQ in the following manner: the number of days with a 
missed dose will be divided by the number of days in the time period and then multiplied by 100. Adherence 
rates will be calculated for both the week and the month prior to assessment visit and for the study period.   Given 
a sample size of 30 subjects with 20% attrition and two-sided Type I error of 0.05, for paired t-tests we will have 
power of 0.80 for effect sizes of at least 0.597.  For correlations, power of 0.80 is achieved for a two-sided test 
of correlation being zero when the magnitude of correlation is at least 0.51. Hence, there is sufficient power to 
detect moderate level mean differences and correlation values.  For the assessment of mean injection frequency, 
suppose 6 prescribed injections in 6 months, with a standard deviation of 1.2 (20% of prescribed injections).  
Then, if a sample mean of 5.28 or higher is observed (88%), a 95% two-sided confidence interval will not contain 
4.8, the 80% threshold, This would provide evidence that the percentage of injection frequency is higher than 
80%.  Note that adherence levels of 80% or higher are widely considered to be “acceptable” adherence in the 
research literature. The mean LAI injection frequency in our previous pilot work involving LAI + CAE in homeless 
patients with schizophrenia exceeded 90% of prescribed injections at 6-month follow-up.  We thus expect to 
statistically establish that the mean LAI injection frequency in this bipolar sample who are not homeless is above 
the 80% threshold. 
 
Data analyses will be performed using the Statistical Analysis System (SAS) (SAS Institute, Cary, NC, 2002).. 
For Aim 1, change in TRQ from baseline to 24 weeks will be assessed with a paired t-test or Wilcoxon signed 
rank test.  For mean LAI injection frequency, we will construct 95% confidence intervals.  Exploratory longitudinal 

 
9 
models of adherence will be considered as well.  We may represent adherence as a binary outcome, indicating 
whether or not an adherence threshold has been met (e.g., 80% adherent), particularly if adherence levels are 
highly skewed. Exploratory logistic regression through generalized estimating equations (GEE) or generalized 
linear mixed models for binary outcomes will thus be considered for assessing effects of time. Time may be 
modeled with a slope parameter or treated as a categorical variable.  Age, race, duration of illness, and/or gender 
will be considered as possible covariates.  In addition, we will compare corresponding TRQ and SimpleMed 
pillbox adherence levels. Correlation between the adherence measures will be estimated and Bland-Altman plots 
will be generated (Altman 1983).   
     Aim 2 will evaluate change from baseline to 24 weeks in TRQ, psychiatric symptoms (BPRS, MADRS, YMRS, 
CGI) in a similar manner as in Aim 1.  For Aim 3, change in the outcome variables and other secondary measures 
in the proposed study vs. historical controls (the previously conducted CAE + LAI pilots) will be compared through 
effect sizes.  In Aim 4, adherence barriers will be evaluated as well. Mean change in symptom rating scales, 
functional level and medication attitudes will be estimated from baseline to the various follow up periods. We will 
explore whether reductions in adherence barriers (e.g., BD knowledge, medication routines, communication, and 
substance) will be associated with changes in adherence behavior. Correlations between respective changes in 
barriers and adherence levels will be computed. In a similar manner, we will also examine whether improvements 
in adherence behaviors correlate with improvements in symptoms, functioning, and medication attitudes.  
 
Study reporting/deliverables:   Reporting on study outcomes will be focused on rapidly available and impactful 
findings.  As the study does not require blinding, it is expected that interim results can be used for new research 
abstract proposals that can be submitted even while the study is ongoing.  It is expected that study results will 
be presented at a minimum of 2-3 suitable scientific venues including (but not limited to): 
 
American College of Neuropsychopharmacology (ACNP) 
 
American Psychiatric Association (APA) 
 
International Society for Bipolar Disorders (ISBD) 
The study findings will also be prepared in manuscript format suitable for submission to an appropriate peer-
reviewed scientific journal with a readership that can use study findings to inform clinical practice and future 
research. Manuscripts given high consideration will include Bipolar Disorders or other publications with a 
similarly-oriented audience target.  
 

 
10 
 
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