Innov Clin Neurosci. 2015;12(11–12 Suppl C):3–17
CNS Drug Compounds
Synthesis of carnitine analogues for inhibition of carnitine palmitoyltransferase
Presenters: Bornstein J, Garneau-Tsodikova S
Affiliations: University of Michigan Life Sciences Institute
Background: Type 2 diabetes (T2DM) carries a markedly elevated risk of cerebrovascular disease. Carnitine plays a key role transporting fatty acids into mitochondria for B-oxidation and decreased levels seen in T2DM are thought to contribute to development of insulin resistance via lipid accumulation in multiple tissues. Unfortunately, the structure and mechanism of carnitine palmitoyltransferase 1 (CPT1), a key enzyme involved in this process, is not well known and could provide useful information to drive future therapeutic developments.
Objective: Herein describes a method to synthesize a diverse array of L-carnitine analogues for CPT1 inhibition with the goal of elucidating key CPT1 components via future structure-activity relationship and protein binding studies.
Methods: A ((S) 2,30 Epoxypropyl) trimethylammonium Chloride epoxide scaffold was synthesized via dropwise addition of ((S)-3-Chloro-2-hydroxypropyl)trimethylammonium chloride to K(t-BuOH). After purification, the resulting compound was treated with acetone cyanohydrin in water to yield a DL-carnitine nitrile. The epoxide and the nitrile were then substituted with various hydrophobic and hydrophilic functional groups.
Results and conclusion: Diverse L-carnitine analogues were synthesized in short synthetic steps with 93%+ yield. In vitro Protein docking and crystal studies of these compounds are currently ongoing and may identify key components of CPT1 positively or negatively affected by the structural modifications to carnitine.
Disclosures: There are no conflicts of interest related to the content of this poster.
A randomized, double-blind, placebo-controlled, four-period, cross-over study assessing the next-day residual effects of flibanserin on simulated driving performance in healthy premenopausal female volunteers
Presenters: 1Kay G, 2Natarajan KK, 1Horohonich S, 1Hochadel T
Affiliations: 1Cognitive Research Corporation; 2Sprout Pharmaceuticals, Inc.
Background: This study compared the next-day residual effects of acute and steady-state nighttime doses of flibanserin (100mg/day and 200mg/day) on simulated driving performance and cognition in healthy female subjects.
Objective: To test for negative effects on measures of next-day simulated driving performance and cognitive testing
Methods: Healthy, premenopausal females (18–-50 years of age) were randomized to flibanserin (100mg or 200mg), zopiclone (7.5mg), or matching placebos the evening prior to testing in a double-blind, placebo-controlled, Latin-square design, with four-way, four-period crossover (n=83). Zopiclone was selected as a positive control for assay sensitivity. On the first day of each treatment period, subjects were dosed with flibanserin, zopiclone, or matching placebo at bedtime. Prior to dosing, they completed a practice drive on the CRCDS-MiniSim and a practice trial on the CogScreen digit-symbol substitution test (SDC). Subjects were awakened approximately seven hours later and within 60 minutes of awakening performed the SDC Test and self-report measures. Subjects then performed the Country Vigilance-Divided Attention (CVDA) driving scenario (100km) approximately nine hours post-dosing.
Results: Compared to placebo, standard deviation of lateral position (SDLP) values were significantly increased following dosing with zopiclone (+3.1cm on Day 2; and +3.5cm on Day 8; both p<0.0001). In contrast, relative to placebo, SDLP values decreased following acute (-2.5cm; p=0.0009) and steady-state (-1.8cm; p=0.0126) dosing with flibanserin (100mg/day). Flibanserin also did not have a deleterious effect on other driving parameters or on cognitive performance.
Conclusions: Therapeutic and supra-therapeutic doses of flibanserin had no negative effect on measures of next-day simulated driving performance and cognitive testing.
Effect of as-needed use of intranasal PH94B on social and performance anxiety in individuals with social anxiety disorder
Presenters: Liebowitz M, Hanover R, Draine A, Lemming R, Careri J, Monti L
Affiliations: The Medical Research Network, LLC
Background: There are no medications approved for use on an as-needed basis for feared social or performance situations for individuals with social anxiety disorder.
Objective: In the present study, PH94B, a novel synthetic neurosteroidal molecule that is administered intranasally in microgram doses, was used as needed during everyday stressful social events.
Methods: Twenty-two subjects were randomized (double-blind) to two weeks of treatment with intranasal PH94B or placebo. Following self-administration of medication prior to an anticipated fearful event, peak levels of anxiety were recorded using the Subjective Units of Distress Scale (SUDS). Subjects were crossed over to the opposite treatment for two weeks. Average peak SUDS during treatment with PH94B and placebo was compared.
Results: Significant differences in favor of PH94B were found on the primary outcome measure. The mean SUDS peak score for all subjects receiving PH94B was 51.1 versus 58.4 for placebo (paired t: 3.09, p=0.006, effect size of 0.658). PH94B showed greater superiority over placebo when placebo was given first than second, likely due to a carryover effect. Looking at just the first two weeks of treatment, PH94B also showed trend superiority to placebo on the Liebowitz Social Anxiety Scale (p=0.07) and a significant difference on the Patient Global Impression of Change (p=0.024).
Conclusion: While further study is needed, these results, combined with earlier findings, suggest that PH94B could represent a useful PRN treatment for social anxiety disorder, and continue to validate the nasal chemosensory system as a novel mechanism for medication delivery.
Disclosures: The study was conducted at the Medical Research Network, a clinical trial facility in New York City owned by Dr. Liebbowtz, and was funded by Pherin Pharmaceuticals, the manufacturer of PH94B. Drs. Liebowitz, Hanover, and Monti have stock options and/or stock in Pherin, and Dr. Monti is the executive VP of Pherin.
A novel clinical trial design to evaluate the safety and efficacy of TAK-375SL in the maintenance treatment of bipolar I disorder: preliminary results
Presenters: Mahableshwarkar AR, Hanson E, Budur K, Macek T, Ogrinc F, Dong X, Hloros E, Tokimoto P, Sachs G
Affiliations: Takeda Pharmaceuticals
Background: A randomized withdrawal design is often used to demonstrate the benefit of long-term treatment to prevent relapse in patients with Bipolar I disorder successfully treated for acute episodes. This standard design, used in the pivotal trials for all treatments that have gained regulatory approval for prevention of relapse, requires discontinuing a treatment and usually defines relapse based on specific threshold scores on selected rating scales for mania or depression (HAM-D, MADRS, and YMRS). This study design, however, has important limitations and the results may not generalize or be relevant to the real-world clinical patient population who might benefit from maintenance treatment.
Methods: We present a novel clinical trial design with TAK-375SL as an add-on treatment to prolong remission in bipolar disorder bipolar I subjects who are stable on their current treatment (either singly or a combination of lithium valproate, lamotrigine, any antidepressant, aripiprazole, olanzapine, quetiapine risperidone, and ziprasidone. TAK-375SL is a sublingual formulation of ramelteon, a melatonin receptor agonist approved for the treatment of insomnia. It is postulated that melatonin receptor agonistic properties may help maintain mood stability and prolong remission periods in patients with bipolar disorder. In this Phase III, randomized, double-blind, placebo-controlled study, the safety and efficacy of 0.1mg, 0.4mg and 0.8mg of TAK-375SL were evaluated for maintenance treatment of bipolar I disorder.
Results: The study screened 1,247 subjects of which 642 were randomized to placebo (164) or TAK-375SL 0.1mg (164), 0.4mg (160), or 0.8mg (154). Baseline demographics were similar across all groups. Low rates of relapse were seen across all treatment groups and there was no statistical difference seen in the number of relapses across the groups, placebo, (n=37; 23.6%), Tak375-SL 0.1mg (n=29; 17.9%), 0.4mg (n=28; 18.2%) and 0.8mg (n=35; 23.5%). A total of 38 subjects reported SAEs: placebo (19) and TAK-375SL 0.1mg (15), 0.4mg (6), and 0.8mg (8); 358 TEAEs were seen in 120 subjects in the placebo group, 319 in 103 subjects in the 0.1mg, 259 in 106 subjects in the 0.4mg, and 295 in 105 subjects in the 0.8mg group respectively.
Conclusion: A Phase III registration study designed with input from the FDA is described. In this study TAK-375SL was not efficacious in prevention of relapse in stable patients with bipolar I disorder. TAK-375SL was safe and well-tolerated.
Cognitive function in vortioxetine clinical trials in major depressive disorder: a meta-analysis
Presenters: 1McIntyre RS, 2Harrison J, 3Loft H, 4Jacobson W, 3Olsen CK
Affiliations: 1University Health Network, University of Toronto; 2Metis Cognition Ltd. & Alzheimer Center, VU University Medical Center; 3H. Lundbeck A/S; 4Takeda Development Center Americas
Background: Patients with major depressive disorder (MDD) often exhibit deficits in cognitive function. This meta-analysis investigated the effect of vortioxetine on cognitive function in patients with MDD.
Objective: To find the effect of vortioxetine on cognitive function in patients with MDD.
Methods: The efficacy of vortioxetine in the treatment of cognitive dysfunction in MDD was evaluated in three eight-week, placebo-controlled studies (NCT01422213, NCT01564862, NCT00811252), two of which included duloxetine as an active reference for assay sensitivity. The Digit Symbol Substitution Test (DSST) assessed cognitive function and the Montgomery-Åsberg Depression Rating Scale (MADRS) assessed depressive symptom severity. To evaluate the independent effect of treatment on cognition, we adjusted for the effect of depressive symptoms assessed by MADRS. Standardized effect sizes (SES) were used.
Results: DSST changes from baseline at Week 8 (SES based on number of correct symbols) versus placebo (FAS, ANCOVA, LOCF), without adjusting for change in MADRS total score, were vortioxetine 10/20mg: 0.254 (p<0.05, n=175), duloxetine: 0.176 (NS, n=187) (NCT01564862); vortioxetine 10mg: 0.477 (p<0.001, n=193), vortioxetine 20mg: 0.482 (p<0.001, n=204) (NCT01422213); vortioxetine 5mg: 0.265 (p<0.05, n=152), duloxetine 0.073 (NS, n=144) (NCT00811252). After adjustment for MADRS, vortioxetine separated from placebo (p<0.0001), SES=0.24 in the meta-analysis of all three studies. For the two studies with duloxetine, vortioxetine separated from placebo (p<0.05), SES=0.19, whereas duloxetine did not separate from placebo (p=0.6171), SES=0.04. The difference between vortioxetine and duloxetine was statistically significantly (p<0.05) in favor of vortioxetine, SES=0.16.
Conclusion: In patients with MDD, vortioxetine statistically significantly improved the performance on the DSST compared to placebo in the meta-analyses, both with and without adjusting for the MADRS.
Disclosures: RS McIntyre is a consultant to and receives speaker fees from Takeda, Lundbeck, AstraZeneca, Eli-Lilly, Janssen, Otsuka, Sunovion, Allergan, and Pfizer. J Harrison has received honoraria and paid consultancy from Lundbeck A/S and the Takeda Pharmaceutical Company, Ltd. H Loft and CK Olsen are employees of H. Lundbeck A/S. W Jacobson is an employee of the Takeda Pharmaceutical Company, Ltd. Funding by: H. Lundbeck A/S and Takeda Pharmaceutical Company, Ltd.
Efficacy and safety of ITI-007 in clinical studies of schizophrenia
Presenters: Vanover K, Davis R, O’Gorman C, Saillard J, Weingart M, Mates S
Affiliations: Intra-Cellular Therapies, Inc. (ITI)
Background: Schizophrenia is a serious mental illness that exerts a high toll on patients’ lives and caregivers. More efficacious, safer treatments are needed. ITI-007 is in late-stage clinical development.
Objectives: Through synergistic actions via serotonergic, dopaminergic and glutamatergic systems, ITI-007 represents a novel approach to schizophrenia treatment.
Methods: ITI-007-005 is a four-week Phase II trial; 335 patients were randomized to receive one of four treatments orally once daily: ITI-007 (60mg or 120mg), risperidone (positive control), or placebo. ITI-007-301 is the first of two Phase III trials, wherein 450 patients were randomized to receive either ITI-007 (60mg or 40mg) or placebo for four weeks. In the second Phase III trial ITI-007-302 (ongoing), approximately 580 patients are planned to be randomized to receive ITI-007 (60mg or 20mg), risperidone (positive control), or placebo. The primary efficacy endpoint is the Positive and Negative Syndrome Scale (PANSS) total score change from baseline versus placebo.
Results: ITI-007 60mg significantly improved schizophrenia symptoms on the primary endpoint (least squares [LS] mean change -13.2 points vs -7.4 points; P=0.017, MMRM, ES=0.4) in Phase II. Risperidone (4mg) differed from placebo on the PANSS total demonstrating assay sensitivity. ITI-007 was safe and well-tolerated. Secondary analyses indicated improved negative symptoms and symptoms of depression. An update from the Phase III program will be presented.
Conclusion: ITI-007 represents a novel direction for the treatment of schizophrenia with unique pharmacologic properties and a differentiating clinical profile. The benefits of ITI-007 in schizophrenia continue to be elucidated in this late-stage clinical program.
Disclosures: ITI-007 is an investigational drug in development funded by Intra-Cellular Therapies, Inc. (ITI). KEV, CO’G, JS, MW, and SM are employees of ITI. RED is a paid consultant to ITI.
High-resolution actigraphy and advanced signal processing objectively quantifies nocturnal scratching events in patients with atopic dermatitis
Presenters: 1Peterson B, 2Almazan T, 2Craft N 1 Moreau A, 1Anderer P, 1Cerny A, 1Ross M
Affiliations: 1Philips Healthcare; 2Science 37
Background: Atopic dermatitis is an inflammatory skin condition that is associated with pruritus. A method for objectively quantifying nocturnal scratching events could aid in the development of therapies for pruritic disorders.
Objective: To assess the accuracy of an objective, non-invasive method to quantify nocturnal scratching events in patients with atopic dermatitis using high-resolution actigraphy.
Methods: Nine adults with atopic dermatitis and three healthy adults were enrolled in the study. High-resolution actigraphy devices were placed on both wrists and worn during one night in a sleep lab that included video recording. Time and duration of scratching events were scored by a trained medical observer watching the video. The subjects also completed scratching questionnaires in the morning. The actigraphy devices captured three-dimensional acceleration data at 100Hz. A combined neural networks and features analysis algorithm was developed to distinguish scratching episodes from other movements.
Results: Total nighttime scratching events detected by the wrist-worn actigraphy device data correlated well with scratching events determined by scoring the videos (r=0.96 p<0.001). Among the subjective assessments, the visual analog scale provided the best correlation with the video scoring but it was not very strong (r=0.77, p<0.01).
Conclusion: In this initial study, nocturnal scratching determined by high-resolution actigraphy and advanced signal processing correlated well with scratching episodes identified visually. Additional data are needed to confirm the validity of this approach. The ease of actigraphy use in a home setting makes it a potentially useful tool in clinical trials to evaluate new therapies for atopic dermatitis.
Probabilistic sleep models as improved EEG-based biomarkers for subjective sleep quality
Presenters: 1,2Dorffner G, 1,3Aydemir Ö
Affiliations: 1Medical University of Vienna, Austria; 2The Siesta Group; 3Karadeniz Technical University
Background: Electroencephalography (EEG), as part of polysomnography (PSG), together with other electrophysiological measurements, is the gold standard biomarker for measuring sleep. Correlations of PSG variables to subjective sleep quality assessments are very poor.
Objective: In this study we explored novel probabilistic sleep models based on EEG data to prove that such correlations can be increased by extracting more information about sleep microstructure.
Methods: We applied a previously developed probabilistic sleep model (PSM) to data from 270 subjects and calculated proper descriptive variables (e.g., area under the curve, entropy, spectral content) from the resulting probabilistic curves describing the main sleep processes. We then calculated linear regression models on optimized subsets of such variables regressing on a standard subjective sleep assessment score. For comparison, we performed the same procedure with variables from traditional PSG-based sleep variables (e.g., sleep efficiency, percentage in each sleep stage).
Results: Results show that Pearson correlation coefficients between sets of probabilistic sleep variables and subjective sleep quality are significantly higher than for any corresponding set of traditional sleep variables (by 35% on average, r=0.40±0.042 for PSG to r=0.52±0.035 for the PSM).
Conclusion: This work confirms that a EEG-based description of human sleep that goes beyond traditional sleep stages can extract more information about sleep and thus constitutes a better biomarker for measuring how well a person slept subjectively. This can be an important tool for early clinical trials on hypnotics.
Disclosures: Georg Dorffner is a part-time employee of The Siesta Group GmbH.
Patient Assessment, Scales, and Tools
Examining placebo effects on MATRICS battery measures in schizophrenia cognition clinical trials
Presenters: 1,2Keefe R, 2Davis V, 2Atkins A, 3Harvey P, 4Lombardo I, 5Bugarski-Kirola D, 6Reid C
Affiliations: 1Duke University; 2NeuroCog Trials; 3University of Miami; 4Axovant Sciences Inc.; 5F. Hoffmann-La Roche Ltd; 6Roche Products Limited
Background: The Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Battery (MCCB) is described as the gold standard by members of the psychiatry divisions of the US FDA and the European Medicines Agency.
Objective: The psychometrics of the MCCB have been increasingly well established. However, the magnitude and predictors of improvement in sequential assessments with placebo treatment is unknown.
Methods: We combined data from 12 MCCB studies assessing 753 placebo-treated patients with schizophrenia over 4 to 56 weeks. Change from baseline was investigated using a mixed-effects model of repeated measures. Predictors evaluated included demographics, baseline characteristics and symptoms. Practice effects were examined in a model including seven studies (N=498) that measured cognition at screening.
Results: The overall mean change in the MCCB composite over 56 weeks, adjusting for baseline score, study and their interaction, was 1.8±0.20 T-score points. Mean change scores for the 10 subtests comprising the MCCB ranged from 0.2±0.33 (MSCEIT) to 2.3±0.35 (Trail Making) T-score points. Patients with higher baseline PANSS Marder anxiety/depression factor scores were more likely to show improvement on the MCCB composite (p=0.004). Practice effect prior to randomization was negatively associated with placebo response (p<0.001).
Conclusions: Improvement on the MCCB under placebo conditions was generally consistent with known practice effects. Results suggest that placebo effects beyond known practice effects are not a major barrier for designing cognitive impairment treatment trials in patients with schizophrenia. Studies with a higher number of assessments are susceptible to greater improvement in the placebo group.
The tablet-based Brief Assessment of Cognition (BAC App) for schizophrenia
Presenters: 1,2Keefe R, 1Atkins A, 1Davis V, 1Tseng T, 1Vaughan A, 3Harvey P, 4Patterson T, 5Narasimha M
Affiliations: 1NeuroCog Trials; 2Duke University Medical Center; 3University of Miami Miller School of Medicine; 4University of California, San Diego, School of Medicine; 5University of South Carolina School of Medicine
Background: The Brief Assessment of Cognition in Schizophrenia (BACS) is a pen-and-paper cognitive assessment tool that has been used in hundreds of research studies and clinical trials, and has normative data available for generating age- and gender-corrected standardized scores.
Objective: A tablet-based version of the BACS called the BAC App has been developed. This study compared performance on the BACS and the BAC App in patients with schizophrenia and healthy controls.
Methods: Forty-eight patients with schizophrenia and 50 demographically matched healthy controls from three academic research centers were assessed with the BACS and the BAC App.
Results: In both groups, the distributions of standardized composite scores for the tablet-based BAC App and the pen-and-paper BACS were indistinguishable, and the between-methods mean differences were not statistically significant. The discrimination between patients and controls was similarly robust with the BAC App (d=1.34) and the BACS (d=1.24). The between-methods correlations for individual measures in patients were r>0.70 except Token Motor (r=0.43) and Tower of London (r=0.61). In patients, performance between the test methods was not significantly different on any test except the Token Motor Test. When data from the Token Motor Test were removed, the between-methods correlation of composite scores improved to r=0.88 (df=48; P<0.001) in healthy controls and r=0.89 (df=46; P<0.001) in patients, consistent with the test-retest reliability of each measure.
Conclusion: The tablet-based BAC App generates results consistent with the traditional pen-and-paper BACS. These data support the notion that the BAC App can now be used in clinical trials and clinical practice.
Disclosures: Richard Keefe receives royalties for the BACS and the BAC App and is the owner of NeuroCog Trials, which provides commercial services to support both instruments. Alexandra S. Atkins, Vicki Davis, Tina Tseng, and Adam Vaughan are employees of NeuroCog Trials. Philip Harvey receives royalties for the BACS and the BAC App.
Relationship between the Positive and Negative Syndrome Scale (PANSS) and a self-reported level of functioning, measured by the Specific Level of Functioning Assessment Scale (SLOF) among patients with schizophrenia
Presenters: 1,2Opler M, 1Lam J, 1Tatsumi K, 1,3Khan A, 1,4Rothman B
Affiliations: 1ProPhase LLC; 2New York University, School of Medicine; 3Nathan S. Kline Institute for Psychiatric Research, Manhattan Psychiatric Center; 4Teachers College/Columbia University
Background: Salient impairment in everyday functional skills, such as basic self-care, interpersonal relationships, and occupational functioning, are present in patients with schizophrenia (Murray CJL et al., 1997; Wiersma D et al., 2000).
Objectives: However, there is often a discrepancy between objective and subjective evaluations of functional impairment for patients diagnosed with psychotic disorders (Bowie et al., 2007). This study aimed to examine the relationship between clinician perceptions of psychiatric severity and patient-reported perceptions of functional impairment.
Methods: Data analyzed in this study was originally collected for the Validation of Everyday Real-World Outcomes (VALERO) study. Inpatient adults with a diagnosis of schizophrenia (N=239) were evaluated with the PANSS by clinicians. Using a modified version of the SLOF, patients also reported their own perception of their level of social functioning. On the basis of PANSS anchor/behavioral descriptors, each PANSS individual item was dichotomized as showing either functional impairment (coded as “1”) or no functional impairment (coded as “0”). These items were then summed to create a PANSS functional impairment score. Via correlational analyses, the only significant relationship found between these two measures was between the PANSS total functional impairment score and the SLOF interpersonal relationships subscale score (r= -0.148, p<0.05).
Conclusion: This suggests that patients with high levels of psychiatric severity are most likely to report only impairments in social functioning. In other words, patients may be less aware of deficits in other domains of functioning that exist. Further analyses will follow.
Rosenberg Hassman Mood Scale: assessing understanding of impairment self-rating instructions
Presenters: Rosenberg L, Marini T
Affiliations: Center for Emotional Fitness
Background: Problem Statement: The Rosenberg Hassman Mood Scale (RHMS) is a frequency-based depression severity scale. To meet DSM-5 criteria for a major depressive episode (MDE), the depression-related “symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.” “Symptoms” refer to the nine biologically based symptoms of an MDE listed in DSM-5. The RHMS expanded the nine DSM-5 symptoms into 23 depression topics. Each topic is sub-divided into 5 to 9 synonyms resulting in 163 possible symptoms of depression. Accurately correlating the nine symptoms of an MDE to distress or impairment has historically been difficult; accurately correlating the 163 RHMS symptoms in the 23 RHMS topics to the three distress/impairment questions is likely to be difficult as well.
Objective: To measure the understandability of the RHMS distress/impairment questions’ instructions
Methods: After completing the RHMS, 20 adult subjects with MDE were instructed to complete the RHMS impairment questions using the instructions as they now appear. 20 additional subjects used Instruction Variation 1 and 20 used Instruction Variation 2. All subjects were then given the same five-question multiple choice quiz. Quiz responses determined the level of accuracy of the subjects’ understanding of the various instructions.
Results: The RHMS instructions for the three distress/impairment questions lack clarity in explaining the correlation of symptoms to distress or impairment. Variations 1 and 2 appear to demonstrate improved understanding of the correlation of symptoms to distress or impairment. Statistical analysis will be presented.
Utilization of baseline patient characteristics to determine minimal clinically important differences (MCID) and clinically relevant treatment response for the UCSD Performance-Based Skills Assessment (UPSA) in 600 patients with major depressive disorder (MDD)
Presenters: 1Harvey P, 2Jacobson W, 2Merikle E, 2Zhong W, 2Nomikos G, 3Olsen CK, 3Christensen MC
Affiliations: 1University of Miami Miller School of Medicine; 2Takeda Development Center Americas; 3 H. Lundbeck A/S
Background: The UCSD Performance-Based Skills Assessment (UPSA) has been extensively utilized in patients with schizophrenia and bipolar disorder to measure functional capacity.
Objective: This post-hoc analysis of NCT01564862 reports the psychometric properties of the UPSA in patients with MDD in an outpatient clinical trial setting.
Methods: Patients with MDD (18–65yrs, MADRS ?26) with self-reported cognitive dysfunction were enrolled in an eight-week, double-blind, placebo-controlled study. Clinical outcomes included DSST, CGI, PDQ, WLQ, MADRS, and UPSA. Construct validity was examined via baseline correlation analyses of the UPSA Composite Score (“UPSA,” comprising UPSA and UPSA-B in English- and non-English-speaking patients, respectively) and clinical outcomes. Anchor-based (CGI-I ?2) and distribution-based (one-half SD) analysis methods were used to establish a responder definition.
Results: The mean UPSA score at baseline was 77.8 (SD=12.89). Significant baseline correlations (p<0.05) were observed between the UPSA and duration of current MDE (r=0.10), age (r=-0.13), education (r=0.28), DSST (r=0.36), and WLQ (r= -0.17), but not MADRS or PDQ. MADRS only correlated (p<0.05) with duration of current MDE (r=0.13) and PDQ (r=0.32). The anchor-based approach resulted in an estimate of +6.7 for a responder definition on the UPSA, which was supported by the distributional-based approach (mean +6.1).
Conclusion: UPSA correlated with cognitive performance (DSST) and workplace productivity (WLQ) but not mood (MADRS) or subjective cognitive functioning (PDQ), supporting the construct validity of UPSA for functional capacity in MDD independent of mood symptoms. Anchor-based and distributional analyses suggest a +7-point improvement in UPSA as a responder definition for treatment response.
Disclosures: Harvey PD has served as a consultant to AbbVie, Boehringer Ingelheim, Forum Pharma, Genentech, Lundbeck Pharma, Otsuka America, Roche Pharma, Sanofi, Sunovion, and Takeda Pharma in the past three years. Jacobson W owns stock in Takeda, Pfizer, and United Health and is a full-time employee of Takeda Development Center Americas. Merikle E, Zhong W, and Nomikos G are full-time employees of Takeda Development Center Americas. Christina Kurre Olsen is a full-time employee and stock owner in H. Lundbeck A/S. Christensen MC is a full-time employee of H. Lundbeck A/S. Funding provided by H. Lundbeck A/S and Takeda Pharmaceutical Company, Ltd.
The Symptom of Trauma scale (SOTS): a new tool for measuring symptom severity in PTSD
Presenters: 1,2Opler M, 3Ford J, 4Mendelsohn M, 5Opler L, 4Kallivayalil D, 4Levitan J, 5Pratts M, 6Muenzenmaier K, 7Shelley AM, 1Grennan M, 4Lewis Herman J
Affiliations: 1ProPhase LLC; 2New York University, School of Medicine; 3University of Connecticut Health Center; 4Victims of Violence Program, Cambridge Health Alliance/Harvard Medical School; 5St. Joseph’s Hospital Health Center; 6Albert Einstein College of Medicine; 7Accretive, LLC
Background: The Symptoms of Trauma scale (SOTS) is a 12-item, interview-based clinician rating measure assessing the severity of a range of trauma-related symptoms.
Objective: This pilot study evaluated its use and psychometric properties in an outpatient setting providing treatment to survivors of chronic interpersonal trauma.
Methods: Thirty participants completed self-report measures of posttraumatic stress symptoms, depression, dissociation, self-esteem, and affect dysregulation, and separately participated in a semi-structured interview based on the SOTS, which was conducted by two trained interviewers.
Results: SOTS composite severity scores for DSM-5 PTSD and PTSD dissociative sub-type, ICD-11 complex PTSD (sPTSD), and total traumatic stress symptoms generally had acceptable internal consistency (Alpha=0.70–0.73) and interrater reliability (ICC=0.88–0.95). Evidence of convergent and discriminant validity was found for the SOTS composite PTSD scores, although potential limitations to validity requiring further research and measure refinement were identified for the SOTS composite cPTSD score and the hyperarousal, affect dysregulation, and dissociation items.
Conclusion: Both interviewers and interviewees described the interview as efficient, informative, and well tolerated. Implications for clinical practice and research refinement of the SOTS are discussed.
Rater Training and Rater Assessment
Examining the impact of ongoing assessment feedback on site rater performance: does our work matter?
Presenters: Baldwin K, Avrumson R, Cohen E, Friedmann B, Carbo M, Glaug N, Komorowsky A, Rapsomaniki E, Rock C, Murphy M
Affiliations: Worldwide Clinical Trials
Background: Rater training companies provide ongoing data surveillance to ensure scale administration, scoring, and protocol parameters are maintained. However, there is a paucity of data exploring whether site raters improve with ongoing data surveillance.
Objective: While Targum (2006) and Busner et al. (2012) demonstrated the effectiveness of ongoing training in reducing overall rater errors within industry-sponsored clinical trials, the current study adds to the literature by examining whether external rater feedback impacts individual rater accuracy as well as protocol adherence.
Methods: Data from a global 26 week clinical trial evaluating negative symptoms and cognitive function in outpatient schizophrenia subjects were evaluated retrospectively. Previously qualified and credentialed site raters submitted all screening and baseline diagnostic and symptom severity scales to external, expert clinicians who reviewed the scales to detect raters’ errors based on their not following scales’ administration and scoring conventions and protocol instructions.
Results: Data were derived from 27 raters across 27 centers in 137 patients over 217 visits. Statistically significant findings were observed for the effect of feedback on rater accuracy (ANOVA; p<0.0001). Based on a mixed model for repeated measures (with number of errors logarithmically transformed) the number of errors per rater was 4.0 [95% CI, 2.7, 5.8] before feedback, and 1.2 [1.0, 1.5] after feedback, representing a statistically significant reduction of 2.8 [1.7, 4.3] errors per visit per rater.
Conclusion: Though a causal relationship cannot be inferred without a concurrent control group, results suggest a significant relationship between ongoing assessment feedback and rater performance.
Disclosures: All authors are full-time employees of Worldwide Clinical Trials and have no conflicts of interest.
Improving data quality through an integrated approach to eClinical data collection, rater training, and rater performance monitoring
Presenter: Dallabrida S
Background: Rater training has become an essential step in protecting the quality of clinician-reported (ClinRO) and observer-reported outcome (ObsRO) data.
Objective: This poster evaluates current methods of rater training and describes a new generation of rater training initiatives specific to electronic data collection.
Methods: To evaluate current modes of rater training for paper instruments, we conducted literature searches, conducted secondary market research on global rater training providers and interviewed professional rater trainers to identify process inefficiencies and instructional design shortcomings.
Results: The current paradigm for rater training revealed repetitive instruction, inconsistent proof of rater training, an inability to gate raters from clinical subjects, and an extraordinary length of time required by raters to simultaneously execute the paper instrument while following instrument instructions. It was determined that these processes could not be replicated efficiently for the electronic implementation of instruments.
Conclusion: A new model for electronic rater training has been developed and tested to consolidate rater instruction and clinical outcome data within the same database. It unifies rater training with customized instruction on the instrument design and scoring, nuances of electronic implementation, and interviewing techniques. The new model includes rater performance monitoring to detect treatment effect, rater inconsistencies, initiate remediation, and gate raters to study participants.
Disclosures: The presenter is an employee of ERT.
Is a computer-simulated rater good enough to administer the Hamilton depression rating scale in clinical trials?
Presenters: Sachs G, DeBonis D, Wang X, Epstein B
Affiliations: Bracket Global, LLC
Background: Are Hamilton depression rating scale scores obtained by a computer simulated rater within the range expected from site-based raters?
Objectives: Concern about the high rate of failed clinical trials and the costs associated with trials’ experimental treatments fuel the desire for better measurement techniques.
Methods: The presenters developed a computer-simulated rater (CSR) based on the scripting and rules taught to site-based raters training to administer and score the HDRS-24. Blinded data were harvested from a double-blind, placebo-controlled, industry-sponsored study. At each study visit that required the site-based rater to administer the HDRS-24, the CSR administered the HDRS-24 as a separate independent rating.
The CRS conducts an interactive interview directly with the study subject. An interview algorithm selects probe questions based on the subject’s last response, and a scoring algorithm maps the subject’s responses to a unique anchor point. Site-based raters administering the HAM-D had to meet sponsor requirements for experience and education.
Results: Results were obtained from the Bracket HAM-D-24 blinded study dataset, which included 737 subjects, 112 raters, and 3,180 administrations of the paired rater and computer interviews made over the course of a 16-week, double-blind, placebo-controlled clinical trial. SBR and CSR produced similar mean scores across all time points examined in an actual global RCT. ICCs ranged from 0.60 at the baseline visit to 0.85 at late study visits.
Conclusion: It is unclear whether the improvement in the ICC observed after randomization reflects subject practice effects, changes in variance over the course of the study, or alteration in rater or respondent behavior after determination of eligibility. Computer-administered scales may offer important advantages not because a CSR is a better than the average site-based rater, but because the computer is consistent, fast, and frugal. By simulating the judgment of a human rater the CSR offers an alternative to reliance on self-report measures.
Disclosures: All authors are full time employees of Bracket.
Identical scorings of the PANSS vary significantly between different study types
Presenters: Kott A, Daniel DG
Affiliations: Bracket Global, LLC
Objective: To examine whether there are differences in the presence of identical scorings (IS) between different study types.
Methods: We have analysed data pooled from 13 double-blind schizophrenia clinical trials. We defined these four study types: Acute—short term with acutely exacerbated subjects, Negative—focusing on negative symptoms, Maintenance—relapse prevention, and Non-acute—stable, non-acute, non-predominantly negative subjects. For each study type we calculated the proportions of IS (all 30 PANSS items identical across consecutive visits) and tested for significant differences between study types using the chi-square test.
Results: The dataset consisted of 53,941 visits (Acute—11,804; Maintenance—5,458; Negative—17,179, and Non-acute—19,500). The mean (SE) percent of IS by study type were Acute: 2.21 (0.14); Maintenance: 2.89 (0.23); Negative: 6.19 (0.18); and Non-acute: 4.10 (0.14), respectively. The chi-square test (chi2(3)=306, p<0.001) indicated significant association between study type and presence of IS.
Conclusion: The highest proportion of IS occurred in the negative and non-acute studies where raters might have anticipated less change. The high percentages of IS are indicative of raters in large number of cases failing to detect the expected changes in subjects’ symptom severity. This may represent a serious problem for potential drug placebo separation. Reasons for this inability to detect change may be multiple, ranging from PANSS not being an appropriate scale for these types of studies, inadequate raters’ understanding of PANSS items, expectation bias, up to rating sloppiness or misconduct. In any instance of IS present, the individual case should be carefully examined and a tailored remedial plan should be developed.
Disclosures: Dr. Kott and Dr. Daniel are full time employees of Bracket Global, LLC.
A methodology for evaluating clinical trial sites and raters based on performance data
Presenters: Miller D, Feaster HT, Allen S, Gratkowski H, Butler A
Affiliations: Bracket Global, LLC
Objective: A methodology was developed to evaluate historical experience and clinical outcome administration performance data as a mechanism to enhance site and rater selection.
Methods: A proprietary database of sites and raters who had participated in recent clinical trials (trailing 3 years) was compiled, with sites and raters required to have a minimum number of trials. The database included historical experience with ratings scales, performance data on certification programs, and performance data based on quality assurance programs implemented to ensure quality ratings were performed during a clinical trial. Quality assurance measures included surveillance methodologies. Each rater’s experience, certification and quality assurance measures were assigned weighted numerical values. Each rater at a site contributed to the site’s overall score. Once sites were categorized, a clinical review was conducted of the data and rankings based on experience with sites and raters as well as overall performance.
Results: A total of 13,600 unique raters covering 2,195 research sites in 49 countries and across 21 different clinical trials were evaluated. Performance data included 27,277 scale administrations resulting in 10,188 rater contacts for potential quality assurance issues. A total of 4,352 of the contacts resulted in remedial action. A total of 2,198 sites were given a final classification based on those criteria. A total of 1,223 (56%) were classified as “Recommended,” 873 (40%) were classified as “Moderately Recommended,” and 102 (5%) were classified as “Not Recommended.” From the pool of evaluated sites, one site that was classified as “Not Recommended” was included in the trial. A total of 77 sites classified as “Recommended” were selected, and 20 “Moderately Recommended” sites were selected. A total of 25 sites that were not previously evaluated were also selected.
Conclusion: Systematic tracking and evaluation of experience and performance data are routinely utilized to assist in clinical trial site feasibility processes. These data frequently rely heavily on past patient recruitment and site data monitoring outcomes, and rarely proactively reference past clinical ratings performance data. Utilizing these data may be useful in identifying the highest quality clinical trial sites and raters to conduct future research programs.
Study Protocol and Trial Methodology
Individual PANSS items and study population drive the PANSS/CGI relationship
Presenters: Daniel D, Kott A
Affiliations: Bracket Global, LLC
Background: We have previously reported a mean of 8.0-percent aberration rate in the expected CGI-I/PANSS change correspondence in a review of 45,566 visits in 14 schizophrenia protocols conducted in 39 countries.
Objective: In the current analysis, we evaluated which PANSS items drive the CGI and how the CGI/PANSS relationship varies among acute, stable, and negative symptom clinical trial populations.
Methods: The data were drawn from thirteen multicenter schizophrenia clinical trials, including 41,576 (9,252 acute, 15,285 negative, 4,560 maintenance, and 12,479 non-acute) data points. We analyzed the relationships between changes in CGI-S and the total PANSS, individual PANSS items, subscales, and factor scores using Spearman’s rank correlations by type of study population. Fisher’s Z test was utilized to evaluate differences between the obtained correlations.
Results: Statistically significant correlations were observed between change in individual PANSS items and the change in CGI-S in all study types. In acute, maintenance, and non-acute studies, the strongest correlation with the change in CGI-S was observed in item P1-Delusions, rho=0.63, 0.54, and 0.59 respectively. In studies focusing on negative symptoms, the correlations were generally weaker, and the strongest correlations with the CGI were observed in items N2-emotional withdrawal and N4-passive/apathetic social withdrawal, rho=0.49. Significant differences in correlation coefficients among study types (acute, negative, maintenance and non-acute studies) were observed for most individual PANSS items.
Conclusion: In 2005, Lucht and colleagues elucidated the relationship between total scores of the PANSS and BPRS and the CGI. Our results indicate that changes in individual PANSS items drive the change in the CGI-S score and these items vary by study population. Thus, data quality evaluations that solely evaluate the total PANSS/CGI relationship may be misleading. This has implications for interpretation of the relationship between the PANSS and CGI in both clinical practice and clinical research.
Disclosures: Dr. Daniel and Dr. Kott are full time employees of Bracket Global, LLC.
Enhanced protection against duplicate enrollment in clinical trials by collaboration between two independent research subject registries
Presenters: 1,2,3Efros MD, 1,2Weingard KK, 4,5Shiovitz TM, 4Kaminsky D
Affiliations: 1Verified Clinical Trials; 2Accumed Research Associates PLC; 3Integrated Medical Professionals; 4CTSdatabase LLC; 5California Neuroscience Research
Background: Presently there exists at least four distinct research subject database registries designed to protect against duplicate enrollment in clinical trials. Historically, the detection of duplicate enrollment was contingent upon the research subject having attempted dual enrollment within the single registry selected by the sponsor of the clinical trial. Prior to the current collaborative effort a CRO or pharmaceutical sponsor would typically adopt only one of the registries available for this purpose. While there has been success with this method, collaboration between the two largest and most experienced registries is expected to improve on existing duplicate subject detection. Attempted dual enrollment rates have been most often reported in the range of five percent in clinical trials, approaching up to 10 percent in certain CNS clinical trial indications. Higher rates of attempted dual enrollment are witnessed in healthy volunteer studies. Prior publications and presentations have well established the efficacy of database registries in reducing the incidence of these violations. Two of the largest registries recently began a collaboration to utilize both their databases and detection capabilities in selected clinical trials in an effort to streamline registry services for sites and sponsors and provide superior duplicate subject detection.
Objective: To explore how collaboration between (and possible integration of) two independent research subject database registries may enhance detection rates of duplicate subjects and prevent more protocol-inappropriate subjects from entering clinical trials.
Methods: Beginning in August 2015, the two largest US-based subject registries began work on combining marketing and operational features to allow maximal duplicate subject detection and (eventually) minimize redundancy for sites and sponsors. The results of this early collaboration will be presented.
Results: It is too early in the collaboration to declare inter-operability of two disparate systems. The use of different database inputs (identifiers) and outputs (reports) will require further efforts and testing. However, a combined Subject Registry Authorization Form, covering use of either or both registries, has been approved by several central IRBs. Promotion of the use of both registries, rather than either one individually, to increase duplicate detection, is underway. Methods to allow a single-access point, inter-operability, and a single report covering both registries are currently under discussion.
Conclusion: Use of a research subject database registry has been demonstrated to reduce duplicate enrollment in clinical trials while improving safety and data quality. When possible, at least one of these systems should be employed. By integrating the two largest and most successful research subject databases, significantly increased detection rates and protections against duplicate enrollment are anticipated.
The impact of electronic administration of the ADAS-Cog on clinical trial data quality
Presenters: Feaster HT, Kott A, DeBonis D, Miller D
Affiliations: Bracket Global, LLC
Background: Prior research has demonstrated that ADAS-Cog error rates among clinical trial raters tend to be upwards of 32 percent on initial administration when using the paper version of the scale (Miller et al., 2011).
Objectives: While clinical trials have traditionally relied on paper-based processes, technological advancements are becoming more fully integrated into the conduct of Alzheimer’s disease (AD) clinical trials.
Methods: An enhanced electronic (eCOA) version of the ADAS-Cog was developed for clinical trials to eliminate or minimize common scoring and administrative errors with the goal of improving data quality and rater reliability. The eCOA ADAS-Cog used in this trial was designed to be equivalent to the paper version of the scale, and was augmented with internal logic, standardized instructions and scoring conventions.
Results: 101/1009 (10%) of the eCOA ADAS-Cogs reviewed at the initial Screening visit at multi-national sites contained an error in scoring which required a remediation with the rater. This represents a statistically significant reduction (p<0.0001) in error rates compared to the previously reported 32 percent found with the paper version of the scale.
Conclusion: The use of a eCOA eADAS-Cog, designed with enhancements beyond the paper-pencil version and coupled with an in-study ratings surveillance program to identify errors in scoring, can significantly improve data quality by reducing rater error, enhancing standardized administration/scoring of the scale, and minimizing rater drift over the course of the trial.
Disclosures: All authors are employees of Bracket Global LLC.
A retrospective analysis of the effects of protocol design on completion rates in Phase I studies in subjects with stable schizophrenia or schizoaffective disorder
Presenters: Krefetz D, Brown J, Ridolfi E Affiliations: PRA Health Sciences, Early Development Services
Objective: To study the impact of protocol design on individual completion in Phase 1 studies in subjects with stable schizophrenia or schizoaffective disorder.
Methods: The authors examine the effect of nine trial design variables on individual completion in 11 Phase I trials in subjects with stable schizophrenia or schizoaffective disorder that enrolled at two clinical research sites during the period 2009 to 2014. These 11 trials enrolled 337 subjects and had an overall completion rate of 84 percent (ranging from 75–96%). The variables studied include length of inpatient period, length of outpatient period, longest period between outpatient visits, total time from randomization to final visit, number of outpatient visits, number of arrivals to the site, whether subjects could remain on standard of care antipsychotics, whether the study was placebo-controlled, and the administration route of the investigational product (enteral versus parenteral). Variables are analyzed via a stepwise linear regression analysis to assess the predictive value of each variable with regard to study completion.
Results: The predictive strength of each trial design variable on subject study completion will be presented.
Conclusion: Conclusions can be drawn that inform study design for better subject retention.
Advantages of utilizing an SSRO management model to complement neurocognitive vendor or pharmaceutical sponsor data review
Presenters: Rissling A, Holland D, Parris B, Usala A Affiliations: CTMG Inc.
Background: Neurocognitive rater training and certification coupled with ongoing data review by an external neurocognitive vendor increases data reliability. However, without design reviewed internal quality systems at the investigative site, the quality of neurocognitive data submitted to a vendor is dependent upon each site’s internal processes. External recognition of data issues and implementation of remediation is hence often delayed. The Site Specific Research Organization (SSRO) model applies current Good Manufacturing Practice (cGMP) principles and Adaptive Investigative-Site Management (AIM) to site operational performance as data are obtained and offers advantages to clinical studies employing neurocognitive assessments.
Objective: To introduce specific advantages of utilizing an SSRO management model with AIM in conjunction with neurocognitive vendor or pharmaceutical sponsor data review.
Methods: A neurocognitive preparatory training program is implemented for clinical research coordinators to achieve a thorough understanding of the rationale and methods of the required Sponsor/vendor neurocognitive assessment protocol. An SSRO management service is employed that incorporates AIM, with internal subject matter oversight and quality systems verification.
Results: The model will be evaluated for its ability to provide efficient training and certification; high quality data, decreased data variability, decreased time for query resolution and remediation; and alignment of physician expertise to focus solely on patient safety and assessments that require clinician patient knowledge.
Conclusion: Extensive internal training reinforced by internal quality systems and on-site neurocognitive expert review prior to submission to neurocognitive vendor or pharmaceutical sponsor may provide superior quality data with expedited external neurocognitive review compared to standard external review alone.
Disclosures: Funding for this study was provided by CTMG, Inc. AJ Rissling, D Holland, B Parris, and AL Usala are full-time employees of CTMG Inc.
Understanding site and subject preferences in technologies used to increase the reliability of clinical assessments: a multi-national survey
Presenters: Lytle D, Cohen E, Rock C, Komorowsky A, Friedmann B
Affiliations: Worldwide Clinical Trials, Department of Clinical Assessment Technologies
Background: As technology continues to grow, so does its use within the clinical trial industry. In particular, tablet and computer-based eSource/e-clinical outcome assessment (eCOA) solutions are increasingly being used as tools to enhance the reliability of clinical assessments.
Objectives: While research indicate these technologies improve the efficiency and quality of rater-administered and patient-reported outcome assessments compared to paper instruments (Tiplady, 2014; Williams et al., 2015), little empirical exploration has been conducted investigating how users perceive the technologies in comparison to one another. The current study investigates study coordinator and raters’ views on using a variety of technologies being applied within the industry, as well as feedback they receive from subjects regarding their use of the tools.
Methods: Site coordinators and raters were anonymously surveyed from US and ROW sites. The sites designated to receive the survey had previously participated in numerous psychiatric and neurocognition studies. The site staff were queried about their experiences using these technologies, receiving clinical feedback from electronic devices, as well as their experience with subjects and/or caregivers using these tools.
Conclusion: Obtaining the experiential realities of site staff who utilize assessment technologies is critical to increasing the use and acceptance of the technologies. The goal of this investigation is to better understand site and subject insights regarding these technologies in an effort to address potential shortcoming, leading to their greater usage that will enhance the overall quality of rater assessments.
Trends in the qualification and parameters and demographics of participants completing Human Abuse Liability (HAL) trials
Presenters: Rusch L, Stapleton S, Copeland B
Affiliations: Vince & Associates Clinical Research, Inc. Objective: The primary objective of this study was to assess characteristics of recreational drug users who passed the drug discrimination phase (DDP) of a human abuse liability (HAL) trial. Demographic and substance use profiles are meant to inform future protocol designs on the available subject pool for HAL trials.
Methods: Descriptive data were collected from recent HAL studies, which included over 260 recreational drug users who met DDP criteria. The data collected included recreational drug use history (i.e., most commonly abused drugs, number of lifetime uses) and demographic information. Results: The most commonly abused drugs within this population were ranked and analyzed for total use, mean and median age, and sex discrimination. Overall the order of abuse by brand included Percocet > Clonzapam > Hydrocodone > Alcohol > Lortab > Oxycontin > Vicodin > Opium, and Ambien. In general, the qualification phase supported successful subject selection based on subject completion rates. The mean and median age ranges were 30 and 28 years of age, respectively and most participants were male (88.3%).
Conclusion: The summary of the data collected suggest that within the local geography of the metropolitan Kansas City area, drugs that were used most over the lifetime of enrolled subjects were rank-ordered as DEA Schedule II, Schedule IV, and Schedule III. The demographic data provided outlines the subject type that has high probability of successfully completing a HAL trial.
Disclosures: Authors are employed by Vince and Associates Clinical Research, Inc. Rusch LM holds stock in Cara Therapeutics and Acorda Therapeutics.
Motivating factors for patient participation and completion in psychiatric clinical trials
Presenters: Tireman E, De Vito L, Pina D, Kakar R
Affiliations: Segal Institute for Clinical Research
Background: A growing number of clinical trials are being conducted in nonacademic clinical practice with the goal of providing evidence of the efficacy and safety of new treatment and devices. In order to conduct successful clinical trials, recruitment of appropriate and reliable subjects is of utmost importance. Enrollment of the targeted number of participants is essential to conducting a successful clinical trial. Attitudes of participants toward clinical trials is a significant factor on successful recruitment. With growing of complexity and nuances of psychiatric clinical trials in particular, the attitudes of subjects toward participation may vary based upon health status, trial type and phases of the clinical trials.
Objectives: In order to successfully conduct a clinical trial, the motivating factors of participants must be considered in order to ensure the appropriate and reliable subject pool to obtain the most accurate and valid outcomes. With growing complexity of psychiatric clinical trials, the motivating factors and attitudes of potential subjects can be crucial in avoiding inflated placebo response.
Methods: This is an exploratory survey study using a self-administered survey. One hundred subjects participating in numerous different psychiatric clinical trials completed a questionnaire inquiring about motivating factors of their participation in the trial. The questionnaire consisted of three questions: the first assessing the method of recruitment of the subject and the second and third assessing the motivating factors of participation and completion of the trials in which the subjects were participating. A Chi-square test was used to determine differences in categorical data. A t-test was used to explore differences in the means of variables.
Conclusion. Yet to be determined.
The complexion of risk and error in patient selection for CNS clinical trials: detailed findings from a 16,000-patient eligibility review database
Presenters: Nations K, Reinhold C, Miloslavich K
Affiliations: INC Research
Objective: This analysis aims to elucidate the extent and nature of eligibility decision errors in CNS clinical trials.
Methods: Eligibility review is a process conducted in select trials by a global team of physicians and doctoral-level clinical scientists who review all key screening data before subject are randomized. The reviewers discuss questions/concerns with the investigator, after which the investigator either provides additional clinical history that supports confidence in subject eligibility or the subject is screen failed by the site.
Results: As of August 2015, 16,414 subjects were reviewed for eligibility, covering 38 trials over a five-year period. All subjects were considered qualified by investigators before submission; however, 1,468 (8.9%) were found to be ineligible after review. The rate of findings did not differ significantly between therapeutic areas (psychiatry: 8.4%; neurology: 11.4%; analgesia: 10.4%; F(2,35)=3.13, p=0.06), but did differ between specific indications [F(8,29)=2.43, p=0.04]. However, study-level variability within therapeutic area, and even within indication, suggest that these differences are not meaningful and cannot necessarily predict rate of findings in future trials (all trials range: 0–25.0%). Further, there was no relationship between rate of findings and study size, as measured by number of sites (R2=0.01, p=0.25) and number of subjects (R2=0.03, p=0.99). Additional data will be presented to describe country-level performance, clinical category of findings, and the impact of site experience on patient selection.
Conclusion: This analysis demonstrates that CNS trials are highly susceptible to penetration by unqualified subjects, regardless of therapeutic area and trial size. Light intervention at screening, before inappropriate subjects are randomized, can maximize data interpretability and protect patient safety in clinical trials.
Disclosures: The authors are employees of INC Research, the contract research organization responsible for execution of all trials included in this analysis.
Predicting placebo responders through frame of reference shifts
Presenter: Pashko S
Affiliations: Steven Pashko, LLC
Background: Within dual human information-processing systems theory, two views have been characterized: the rational-cognitive relies on conceptual information and the experiential relies on perceptual information. Self-reports of psychological status vary significantly depending on which dominates; shifting between these views may cause the placebo effect.
Objective: Construct an empirically testable method for the a-priori identification of placebo responders
Methods: The shift can be provoked experimentally through the self-identity/ body swap paradox. In all study subjects, conflicting perceptual inputs cause the unlikely perception that a person’s body has been swapped with a mannequin’s. The shift occurs when conviction in one’s perceptual view overrides their conceptual one. The method was used in a study of pain.
Results: Using this conflict procedure, pain tolerance increased in subjects whose self-identity was shifted. Shifting between reporting: A) perceptual experience plus attendant conceptualizations (e.g., pain + thoughts about it) to B) only the perceptual experience (e.g., pain alone) may be the causal mechanism. Proposed here is that the placebo effect occurs in people who 1) have a higher degree of flexibility in shifting between conceptual and perceptual reporting and 2) initially report from the rational-cognitive (conceptual) view and then from the experiential (perceptual) one.
Conclusion: Determining a person’s propensity (e.g., increased speed and/or completeness) to shift using a “challenge test” (i.e., making the shift stimulus unlike a human form) may yield a method for the a-priori prediction of placebo responders.
Key factors for proactive study start-up and site activation in neuroscience studies
Presenters: Armstrong K, Zarro J
Affiliations: Premier Research
Objective: In the demanding arena of clinical research where deadline and economic pressures are felt by all those who are involved in study execution, it is critically important to ensure rapid, yet thorough, study start-up so that the maximal number of sites are able to begin enrolling at the earliest possible date.
Methods: A suite of neuroscience studies were reviewed to identify and outline the lessons learned and best practices for efficient and effective study start-up.
Results: Key success factors were identified including rapid site identification of those with direct and related neuroscience experience. Rater training can often impact study start-up both on the study level in regards to establishing the requirements for scales management and rater training, as well as on a site activation level with the need for sites to complete the training requirements to start screening. Further, submission deadlines and requirements, both locally and nationally, are critical to meeting planned timelines. Additional factors included the contracting process which is aided by established confidentiality agreements and working experience with the contracting institution requirements of lead sites.
Conclusion: Thorough planning of the key success factors identified is directly related to rapid and efficient study start-up leading to meeting or beating timelines.