Study design
The study measured effectiveness by evaluating efficacy, safety/tolerability and other patient outcomes when used under usual conditions in patients with dementia, stroke, or TBI. Adults with PBA secondary to dementia, stroke, or TBI and a CNS-LS score ≥13 (scale range, 7 [no symptoms] to 35 [maximum]) were enrolled in an open-label, 90-day study of DM/Q 20/10 mg twice daily (once daily during Week 1). Clinical assessments were performed at baseline, Day 30, and Day 90, with a telephone contact at Day 60. This study was conducted in the United States at 74 enrolling sites, from 26Feb2013 to 30Apr2015, according to Good Clinical Practice and the Declaration of Helsinki. The protocol and study materials were approved by the institutional review board at each site and registered on www.clinicaltrials.gov. (identifier: NCT01799941).
Participants
Participants were eligible for enrollment if they had a clinical diagnosis of PBA based on published criteria and a clinical diagnosis of dementia, stroke, or TBI [2]. PBA diagnostic criteria were (1) involuntary or exaggerated episodes of emotional expression (i.e., laughing or crying); (2) development of symptoms that represent a change from the person's usual emotional reactivity occurring subsequent to a specified brain disorder; (3) episodes are incongruent with or out of proportion to the individual's mood state and independent to or in excess of a provoking stimulus; and (4) symptoms are not better accounted for by another disorder, substance abuse, or medication use. Patients were also required to have a CNS-LS score ≥13 [27, 28], the same score required for entry into phase 3 trials of DM/Q for PBA [20–22].
Eligible participants had documented diagnoses of one of the following: dementia, (including Alzheimer’s, vascular, Lewy body, or frontotemporal dementia; ischemic or hemorrhagic stroke; or mild, moderate, or severe non-penetrating TBI. There were no restrictions on types of allowed concomitant medications with the exception of those contraindicated by the US Prescribing Information [16], specifically monoamine oxidase inhibitors (MAOIs), and drugs that both significantly prolong QT interval and are primarily metabolized by CYP2D6 (e.g., thioridazine). Other medications typically used by patients with the studied neurologic conditions (including those that are metabolized by CYP2D6) were allowed with the stipulation that medications for management of dementia, such as memantine or acetylcholinesterase inhibitors should be stable for at least 6 weeks and other neuropsychiatric medications such as anticonvulsants, antidepressants, antipsychotics, anxiolytics, and sedative/hypnotics should be stable for at least 2 months prior to baseline; any medication changes, if deemed necessary, were recorded. Potential participants were excluded if they had severe dementia (Mini-Mental State Examination [MMSE] score <10); stroke within 3 months of study enrollment; penetrating TBI; severe depressive disorder; history or current symptoms of schizophrenia (including psychosis), schizoaffective disorder or bipolar disorder; substance/alcohol abuse in the preceding 3 years; systemic disease, neurologic condition or brain injury that was unstable or rapidly changing within the 3 months prior to enrollment; life expectancy ≤6 months; contraindication to DM/Q use (including known QT interval prolongation); DM/Q use during the previous 6 months; or interventional clinical study participation within the preceding 30 days. Written informed consent was obtained from all participants or from legally authorized representatives.
Outcome measures
Primary measure
The primary outcome was the change in CNS-LS score from baseline to Day 90 (or final visit). The CNS-LS was completed by the patient or the caregiver acting as a patient proxy at Day 1 (baseline), Day 30 (visit 1), and Day 90 or early withdrawal (final visit). The CNS-LS is a 7-item (4 laughing items; 3 crying items), self-report rating scale measure of PBA episode frequency and severity that was validated in persons with ALS and persons with MS and is sensitive to change over time and treatment effects [20–22].
Secondary measures
Secondary measures included PBA episode count for the 7 days preceding each study visit as well as the Clinical Global Impression of Change (CGI-C) and Patient (or Caregiver) Global Impression of Change (PGI-C; 7-point scales ranging from 1 [very much improved] to 7 [very much worse]) based on overall change in the patient’s condition with respect to PBA. In addition, a quality-of-life visual analog scale (QOL-VAS) assessed the degree to which PBA episodes affected the patient’s overall quality of life (11-point scale ranging from 0 [“not at all”] to 10 [“significantly”]) during the past week and a 5-point Likert-type scale rated patient satisfaction with treatment from 1 [very dissatisfied] to 5 [very satisfied]. The Folstein Mini-Mental State Examination (MMSE; 11-item assessment of orientation, memory, attention, and language scored from 0 to 30) was included as a cognitive assessment [29]. As an additional measure, the Patient Health Questionnaire (PHQ-9; a 9-item assessment of depression symptoms with each item rated 0 [not at all] to 3 [nearly every day] based on frequency of occurrence over the past 2 weeks, for a total possible score of 27) was included [30]. Disease-specific functional measures, namely the Neurobehavioral Functioning Inventory and Stroke Impact Scale were assessed in the TBI and stroke cohorts, respectively, and will be reported separately. Caregivers were allowed to complete all assessments except the MMSE for any patients who were unable to do so. The timing of assessments is illustrated in Fig. 1.
Safety
Safety measures included reporting of adverse events (AEs) occurring at any time between study enrollment and up to 30 days after the last dose of DM/Q in the study, as well as vital signs and concomitant medication use.
Statistical analysis
The safety analysis set included all participants who received at least 1 dose of DM/Q. The effectiveness analysis set comprised all participants in the safety set who also met all study eligibility criteria, and completed at least 1 post-baseline CNS-LS assessment. The Medical Dictionary for Regulatory Activities (version 15.1) was used for coding, categorizing, and reporting AEs.
All data were analyzed descriptively. Changes from baseline in ratings at Day 30 and 90 were also analyzed inferentially using one-sample t-tests for rating scale measures (CNS-LS, QOL-VAS, MMSE, and PHQ-9) and a mixed-effects Poisson regression model using number of PBA episodes in the past 7 days as the dependent variable to estimate change in PBA episode counts. The mixed-effects Poisson regression model incorporated age, gender, and time (Day 30 and Day 90) as fixed effects while allowing for individual differences in baseline rate (random-subject effects). The percentage change episode count from baseline to a given visit is 1 minus the appropriate time parameter (λ).
There was no imputation method for missing data; however, if the patient had a Final Visit, that visit was included as the Day 90 Visit. If there was no Final Visit, the Day 30 visit was not carried forward as the subject’s Final Visit.
The primary analysis tested the null hypothesis that the mean change in CNS-LS score from baseline to the Day 90/Final Visit was equal to zero; the 95 % confidence interval (CI) was also reported to enable a descriptive comparison with the CNS-LS change seen in the pivotal phase 3 registration trial (STAR trial) that led to the US approval of DM/Q for PBA [20]. Pearson correlation coefficients were calculated to assess the correlation of CNS-LS scores with other endpoints at baseline, Day 30, and Day 90/Final Visit, as well as correlation of change from baseline in CNS-LS with changes in other measures.
Tests of significance were 2-tailed and carried out at the α = .05 level of significance; all analyses were completed using either SAS v9.2 (SAS Institute Inc., Cary, NC) or Stata v12 (StataCorp, College Station, TX). All patients with data for the given comparison were included.
A power calculation was based on mean (SD) CNS-LS change observed from the pivotal phase 3 trial for the same dose of DM/Q (20/10 mg twice daily): −8.2 (6.1) points vs. placebo: −5.7 (5.3) points. Based on these results, it was determined that a sample size of 100 patients per disease group would provide 80 % power to detect a CNS-LS mean change of −7.45 points (increase of 1.75 points over assumed true placebo mean change of −5.7), or 90 % power to detect a CNS-LS mean change of −7.7 points (increase of 2.0 points over assumed true placebo mean change of −5.7). An interim analysis, conducted after the first 100 patients (regardless of cohort) completed the study, supported these assumptions of magnitude of the effect and indicated that a sample size of 100 per disease group would provide sufficient (≥80 %) power to meet the protocol-specified endpoints. In addition to the results for the entire study population described here, pre-specified analyses for the three distinct diagnosis groups (Dementia, Stroke, and TBI cohorts) were conducted separately and have either been reported in full (Dementia [24]) or have manuscripts in preparation (Stroke [26] and TBI [25]).