Innov Clin Neurosci. 2017;14(11–12)S1—S20.
A Message From the Editor:
Welcome to the annual CNS Summit Abstracts of Poster Presentations supplement to Innovations in Clinical Neuroscience. We are pleased to provide you with this reference guide to some of the innovative research that is being presented during CNS Summit 2017.
This supplement is just a small representation of what has become the premier event each year in drug development. Over 500 leaders in the field are attending this year’s CNS Summit to experience more enlightening talks and innovative reveals than ever before. Here at the CNS Summit, participants will discover the latest advances in pharmaceutical research and development, such as digital biomarkers, mobile medicine, and AI and machine learning, as well as witness the unveiling of several new innovative products and technologies. Additionally, through the proprietary CNS Summit One-to-One Meeting Platform, participants have the unique opportunity to network with the key stakeholders involved in the discovery and development of new compounds and therapies in medicine.
The CNS Summit is committed to collaboration among all entities involved in drug development, and we believe collaboration and data sharing with those involved in research across a wide variety of disease states will create more opportunity for developing better, safer, and more accessible drugs universally and within all areas of healthcare.
In this abstract supplement, we’ve organized CNS Summit 2017 poster abstracts into the following groups for your convenience and easy reference:
- Biomarkers and Imaging
- Digital Tools and Technology
- Investigative Drug Compounds and Therapies
- Mobile Technology
- Patient Assessment and Adherence
- Patient Recruitment
- Placebo Response
- Rater Assessment and Training
- Trial Protocol
You will also find an alphabetical index by author and poster title on pages 20 and 21 of this publication.
We hope you find the CNS Summit 2017 poster abstract supplement informative and that it provides a useful snapshot of the research being presented at CNS Summit 2017. Make sure to mark your calendars for CNS Summit 2018, which will take place November 1 to 4, 2018, at the Boca Raton Resort in Florida. Visit www.cnssummit.org for more information.
Hope to see you in Boca! As always, we welcome your feedback and participation.
Amir Kalali, MD
Editor, Innovations in Clinical Neuroscience
Table of Contents
Biomarkers and Imaging
- KINARM Labs: Better behavior biomarkers using robot-based assessment
- Multiplexed mass spectrometry assay identifies neurodegeneration biomarkers in CSF
Digital Tools and Technology
- Digital technologies in Alzheimer’s Disease Trials
- The Early Psychosis Screener (EPS):a validated accurate web-based self-report screener for prodromal and early psychosis
- Innovation implemented changing Otsuka’s business model through the ePlatform
- Technology-enhanced learning for researchers to support of capacity building in clinical development
Investigative Drug Compounds/Therapies
- Efficacy of vortioxetine in working patients with generalized anxiety disorder
- An intranasal aerosol for social anxiety disorder
- Lamotrigine for ketamine dependence: a randomized, double-blind, placebo-controlled trial
- PH94B nasal spray a PRN treatment for social anxiety disorder: a Phase 3 pilot trial
- A retrospective case-matched study of the efficacy of the MedicaSafe BupeCare Device
- Scientific rationale and clinical development of AXS-05 for neuropsychiatric disorders
- Tolperisone shows no evidence of sedation compared to cyclobenzaprine and placebo in a driving simulation study
- High frequency assessment of mood and cognition in major depressive disorder using the Apple Watch
- Patient engagement text messaging reduces drug interruption and patient dropout in Phase 3 bipolar depression clinical trial
- Project STARR911
- Validity and retest-reliability of sleep measurements using a simple, self-applicable device
Patient Assessment and Adherence
- Criteria satisfied on diagnostic instrument often not confirmed on severity ratings
- Data quality concerns associated with PANSS negative items—an exploratory analysis
- Effect of predominance of negative symptoms at baseline on change in the PANSS total in acute schizophrenia trials—an exploratory analysis
- Real-world patient experience with treatment-emergent sexual dysfunction in depression
- The SAGE-SR: Item development and initial validation of a DSM-5 and SCID-based self-report diagnostic assessment
- Subjects’ knowledge of symptoms that can occur during seizures
- Training, above all other motivators, is preferred by subjects with CNS disorders for motivating them to complete daily questionnaire
- How to scale up recruitment in Alzheimer’s disease clinical trials from 3 to 100 screens a month
- Patient recruitment campaign strategies and effectiveness in a clinical trial of patients with opioid use disorder
- Patient selection for CNS clinical trials: findings from an eligibility review database with a focus on Alzheimer’s Disease trials
- You show me your (I/E) and I’ll show you my (diagnosis): professional subjects changing indications
- Mitigating placebo response in CNS clinical trials: a site-based pilot program
- The power of an educational placebo response video: strengthening subject placebo response awareness across demographic variables and diagnoses
Rater Assessment and Training
- Distribution of performance and incorrect ratings in qualification video scoring
- Identification of Children’s Depression Rating Scale—Revised (CDRS-R) items of particular challenge to raters in child and adolescent depression clinical trials outside of the United States.
- A retrospective analysis of the effects of protocol design on completion rates in outpatient clinical trials in subjects with schizophrenia or schizoaffective disorder
- Towards more efficient methods for COA instrument selection in clinical trials
Biomarkers and Imaging
KINARM Labs: Better behavioral biomarkers using robot-based assessment
Presenters: Lowrey C1, Early S1, Vivian-Scott A2, and Scott SH1,2
Affiliations: 1Queen’s University, 2BKIN Technologies Ltd., Kingston, Ontario, Canada
Background/Objective: Measuring the efficacy of CNS therapeutics is challenging when assessment tools are coarse and have floor/ceiling effects. We developed interactive robotics as a next-generation technology to objectively quantify brain function.
Design: KINARM Labs are clinic-friendly virtual reality robotic platforms that quantify arm movements while subjects perform motor actions. Nine behavioral tasks assess sensory, motor, and cognitive function in about one hour. Automated analyses quantify about 150 metrics of performance relative to a large cohort of controls. Twenty-six subjects who had experienced a stroke were assessed on all tasks in an acute care setting. Recovery patterns were measured by robotic and traditional measures.
Results: Subjects displayed unique phenotypes with different patterns of impairment across sensory, motor, and cognitive domains. In general, robotic measures correlated with clinical measures, although some subjects with perfect clinical measure demonstrated impairments in the robot-based tasks. Ongoing studies highlight broad impairments associated with neurological diseases/injuries, such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS), syringomyelia, multiple sclerosis, and concussion. Studies to identify statistical significant change in each metric are also underway.
Conclusion: This novel technology discriminates and quantifies subtle differences in behavior and neurological impairments in subjects afflicted with neurological injury/disease. KINARM assessments can be incorporated into multi-center trials (e.g., monitoring stroke motor recovery: NCT02928393). Further studies will determine if KINARM Labs can demonstrate a clinical effect with fewer subjects over a shorter trial period.
Disclosures/funding: Dr. Stephen Scott is the inventor of KINARM and CSO of BKIN Technologies.
Multiplexed mass spectrometry assay identifies neurodegeneration biomarkers in CSF
Presenter: Chelsky D
Affiliation: CSO, Caprion Biosciences, Inc., Montreal, Quebec, Canada
Background/Objective: Early detection markers are critical for neurodegenerative diseases since substantial, irreversible damage to the brain occurs by the time of clinical diagnosis. Markers of disease progression are also important, as established clinical assessment tools can require a year or more to detect changes. Current efforts in our laboratory include developing such markers in Alzheimer’s, Parkinson’s, and Huntington’s diseases.
Design: Candidate biomarkers were identified in the literature for each disease, and targeted metabolic response modifiers (MRM) mass spectrometry assays were assembled. In the case of Huntington’s disease, very few candidate markers were known in the literature, so a label-free liquid chromatography–tandem mass spectrometry (LC-MS/MS) discovery study was performed in cerebral spinal fluid (CSF) to identify novel markers.
Results: In each comparison of disease and healthy control CSF samples, a subset of candidate biomarkers was verified. Results are described, including the affected proteins and pathways in each study and the similarities and differences in CSF proteins across the different diseases.
Conclusion: A single, unified assay is now established that enables the multiplexed measurement of 205 neurodegenerative disease-related proteins in 50µL CSF. This can be deployed in support of clinical biomarker and drug development efforts.
Disclosures/funding: This work was funded by the FNIH/Biomarkers Consortium, Michael J. Fox Foundation, and the NIH/NINDS.
Digital technologies in Alzheimer’s disease trials
Presenters: Kalali A1, Richerson S2, and Vahabzadeh A3
Affiliations: 1CNS Summit, 2Therapeutic Science and Strategy Unit, QuintilesIMS, 3Brain Power
Background/Objective: The landscape of clinical trials is evolving to improve the rate of success. This includes leveraging new technologies in multiple areas. Digital technologies in particular have an important role to play in the clinical trials of the future. The pharmaceutical industry has traditionally taken a conservative approach to the adoption of new technologies, with concerns about validity, acceptance by all stake-holders, and regulatory acceptance. This poster presents the areas where adoption of digital technologies creates new opportunities in clinical research.
Design: We compiled a review of new technologies that could have an impact on clinical trials in Alzheimer’s disease (AD).
Conclusion: It is time that clinical trials in AD fully leverage digital technologies already available to researchers. If used effectively, digital technologies can have a wide-ranging positive impact on the conduct of clinical trials in Alzheimer’s disease and their success. Industry-wide collaboration is needed to assess and validate the usefulness new technologies, including their applicability to clinical development. CNS Summit is one community seeking to collaboratively do this. One of the CNS Summit initiatives is the Connected Clinical Trials domain, which is producing a curated registry of connected devices, tools, and services of relevance to clinical trials. Other stakeholders including technology experts, patients, caregivers, investigators, and payers should be fully involved in these collaborative efforts.
Disclosures/funding: Amir Kalali is an advisor to Bracket Global and AiCure. Sarah Richerson is an employee of Quintiles IMS. Arysha Vahabzadeh is an employee of BrainPower.
The Early Psychosis Screener (EPS): a validated, accurate, web-based, self-report screener for prodromal and early psychosis
Presenters: Brodey BB, Girgis RR, Favorov OV, Addington J, Perkins DO, Bearden CE, Woods SW, Walker EF, Cornblatt BA, Walsh B, and Zweede EA
Affiliations: TeleSage, Inc., Columbia, New York State Psychiatric Institute, UNC-Chapel Hill, Department of Biomedical Engineering, University of North Carolina at Chapel Hill, University of Calgary, Hotchkiss Brain Institute, Department of Psychiatry, UNC-Chapel Hill, Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, UCLA, Departments of Psychiatry and Biobehavioral Sciences and Psychology, Yale, PRIME Psychosis Prodrome Research Clinic, Emory University, Departments of Psychology and Psychiatry, Zucker Hillside Hospital, Department of Psychiatry Research, Yale, PRIME Psychosis Prodrome Research Clinic
Background/Objective: Identifying individuals with a high risk of developing a psychotic disorder is critical to many CNS clinical trials. The Structured Interview for Psychosis-risk Syndromes (SIPS) has been the “gold standard” assessment, while the Prodromal Questionnaire-Brief Version (PQ-B) has served as a less rigorous self-report screener. Unfortunately, these assessments suffer from high false positive rates and low predictive value. These deficiencies complicate the efficient conduct of CNS clinical trials.
Design: We aimed to develop and validate a self-report assessment that will accurately identify individuals who are at high risk of developing a psychotic disorder within the next 12 months or who have recently developed a psychotic spectrum disorder.
Methods: The validation included eight academic facilities, 107 nonclinical controls, and 262 clinical participants. All participants were given the PQ-B and EPS items, and all clinical participants were given the SIPS. All participants were followed for 12 to 24 months. A support vector machine classifier was developed to differentiate nonpsychotic from psychotic outcomes. The classifier’s performance was cross-validated using the leave-one-out approach.
Results: The false positive fraction was 51.9 percent for the PQ-B and 11.3 percent for the EPS. Among participants who were identified as clinically high risk using the SIPS, the PPV of the PQ-B, SIPS, and EPS were found to be 22 percent, 23 percent, and 38 percent, respectively.
Conclusion: The EPS appears to be more accurate at identifying individuals who are either prodromal or in the early stages of a psychosis than either the SIPS or the PQ-B. Because the EPS is accurate and brief, it is ideal for screening individuals for admission into clinical trials relating to prodromal and early psychosis.
Disclosures/funding: This research was supported in part by a grant from the National Institutes of Mental Health, which was awarded to TeleSage, Inc. Dr. Brodey is Chief Executive Officer of TeleSage, Inc., and Dr. Zweede is employed by the company as a clinical research specialist.
Innovation implemented: Changing Otsuka’s business model through the ePlatform
Presenters: Nyilas M, Jadhav P, Skubiak T, Whitmore L, Spiller N, Brewer C
Affiliations: Otsuka Pharmaceutical Development and Commercialization, Inc.
Background/Objective: Our objective was to shift to the ePlatform, a full digital trial platform, by implementing technologies to improve the quality and efficiency of our clinical studies to develop solutions for patients much sooner than the traditional model allows.
Design: Our eTrial solution comprises elements including as eSource, eConsent, eScanning, and eSurveillance. Every component has been full tested and validated, in addition to being Health Insurance Probability and Accountability Act (HIPAA) compliant following Food and Drug Administration (FDA) guidelines.
Results: Two individual components of the ePlatform were successfully piloted in 2012. In 2016, Otsuka successfully piloted the full ePlatform in a Phase III study with an added challenge of locking the database within 72 hours of the last patient visit. Upon successful completion of both challenges, Otsuka made the strategic decision to use the ePlatform model for all studies. To date, Otsuka has successfully completed two trials utilizing the full ePlatform. Two Phase III and two Global Phase III trials are live. All additional studies planned over the next 18 months will be utilizing the full ePlatform. The optimization of activities, such as reduced monitoring frequency and narrative authoring, have been cut at least in half, producing tangible business results for the organization as a whole.
Conclusion: As pioneers and leaders in the effort to bridge healthcare and the power of digital technologies, Otsuka’s entire organization is embracing research and development culture. Software has become a new core competency within our organization. By re-engineering our internal capabilities into one integrated system, the execution of a digital clinical trial and submission has become reality.
Technology-enhanced learning for researchers to support of capacity building in clinical development
Presenters: Whitty J1, Whitty S1, Whalen J2, and Sheehan D3
Affiliations: 1Faculty of Capacity Development, 2BTC Network, 3University of South Florida
Background: A global capacity-building program is needed to deal with the complexity of developing new medicines and managing public health in an era when diseases rapidly cross borders and the skills for drug development and the management and analysis of routinely collected data are scarce. Neither the infrastructure nor the number of sufficiently trained personnel is adequate to significantly address this problem, adversely affecting the productivity and quality of life of many citizens.
The challenge is to develop a sustainable ecosystem that supports a researcher’s professional advancement and their organizations capacity development. Members of the Faculty of Capacity employ new tools and advanced methodologies to design, execute, and manage our academic and mentoring programs. Examples include bioequivalence in East Africa, surveillance and control of tuberculosis (TB) in Central Asia, developing a vaccine for arboviruses in Latin America, monitoring malaria resistance, and identifying local communities where HIV is most prevalent. Successful implementation of our programs requires reflective practice supported by a mentorship program.
Intervention or response: The global expansion of internet access presents opportunities to close gaps in professional knowledge and skills through technology enhanced training. Such training can be customized to the specific needs of a program, varying from approaches that blend online with classroom teaching, to complete online courses that are mentor-led. They can also vary from certificate to higher degrees. The Faculty of Capacity Development was formed by faculty from Karolinska Institutet, Sweden, to deliver this type of competency and confidence enhancing training. We want to enable health professionals to deliver the “right interventions to the right population at the right time.” Our mission is to support clinical research, improve professional practice, and save lives. The Foundation for Child Development (FCD) currently runs a program with the Global Health Clinical Consortium, which consists of the World Health Organization Special Programme for Research and Training in Tropical Diseases (WHO TDR), Aeras, Drugs for Neglected Diseases Initiative, Foundation for Innovative New Diagnostics, Global Alliance for TB Drug Development, International AIDS Vaccine Initiative, Infections Disease Research Institute, International Partnership for Microbicides, International Vaccine Institute, Medicines for Malaria Venture, and PATH. This program uses a combination of blended learning and mentoring to achieve higher levels of professional practice and organizational capacity development in a number of low and middle-income countries (LMICs).
Results: Technology-enhanced education upholds the principles of equity in that the quality of content can be guaranteed regardless of where the candidates are located. It drastically reduces costs and allows the learner to pace learning to his or her schedule as much as possible.
Conclusion: Members of FCD have successfully delivered programs that improve clinical research capabilities in developed economies, as well as LMICs. Partners have included Pfizer, Novartis, AstraZeneca, the Drug Information Association (DIA), and the European Union’s Innovative Medicines Initiative. Adapting our structured mentoring program to the needs of clinical researchers in the United States could potentially close many of the gaps in skills and capacity currently developing between the re-search required to introduce new medicines in CNS and the capacity of the industry to successfully carry out that research.
Investigative Drug Compounds and Therapies
Efficacy of vortioxetine in working patients with generalized anxiety disorder
Presenters: Christensen MC1, Loft H1, Florea I1, and McIntyre RS2
Affiliations: 1H. Lundbeck A/S, Copenhagen, Denmark; 2University Health Network, University of Toronto, Canada
Background/Objective: Vortioxetine is an approved antidepressant that has also demonstrated positive effects on anxiety symptoms in subjects with generalized anxiety disorder (GAD). This post-hoc analysis evaluates the effect of vortioxetine in GAD subjects working/pursuing education.
Design: In NCT00744627, 301 GAD subjects were randomized to vortioxetine 5mg or placebo for eight weeks. Efficacy measures included Hamilton Anxiety Rating Scale (HAM-A) total score, response/remission, global functioning (Sheehan Disability Scale [SDS]), and quality of life (Short Form (36) Health Survey [SF-36]). In NCT00788034, 687 GAD subjects were treated open-label with vortioxetine 5- or 10mg for 20 weeks after which subjects in remission were randomized to fixed dose of 5- or 10mg or placebo for at least 24 weeks. Primary endpoint was time to relapse. Analyses were completed in subjects working/pursuing education at study entry and the full analysis set.
Results: In NCT00744627, the effect versus placebo on HAM-A total score was -4.3 (p=0.0005) in working subjects (60% of total), and the effect in the total population was -3.8 (p=0.0001). The effect was greatest in professional (-4.5; p=0.0130) and associate professional positions (-7.6; p=0.0086). Greater effects on response, remission, SDS, and SF-36 were also observed. In NCT00788034, working subjects (69%) randomized to placebo were significantly more likely to relapse than subjects treated with vortioxetine (hazard ratio 2.9; p<0.001). The hazard ratio in total population was 2.7 (p< 0.0001).
Conclusion: The beneficial effects of vortioxetine on anxiety symptoms, functioning, and quality of life are greater in adults with GAD working/pursuing education versus full GAD study population.
Disclosures: Data for this study were from clinical studies sponsored by H. Lundbeck A/S, Valby, Denmark and Takeda Pharmaceuticals Inc., Deerfield, Illinois. I. M.C. Christensen, DrPH, H. Loft, PhD, and I. Florea, MD are employees of H. Lundbeck A/S. R. McIntyre has received research grants and attended speakers bureaus from the following private industries: Bristol-Myers Squibb, Janssen-Ortho, Eli Lilly, Lundbeck, Pfizer, Takeda, Otsuka, and Purdue.
An intranasal aerosol for social anxiety disorder
Presenters: Liebowitz MR1, Salmán E1, Rosenthal N2, Nicolini H3, and Monti L4
Affiliations: 1Medical Research Network, N.Y., N.Y.; 2Capital Clinical Research, Rockville, MD; 3Carracci Medical Group, Mexico City, Mexico; 4Pherin Pharmaceuticals, Los Altos, CA.
Background/Objective: Although social anxiety disorder is a common and sometimes disabling condition, there are no approved pro re nata (PRN) treatments.
Design: A Phase II, multicenter, randomized, double-blind, placebo-controlled, single-dose study of a nanogram dose intranasal aerosol was conducted at three sites. Ninety-one women ages 19 to 59 years with generalized social anxiety disorder underwent single-blind doses of placebo intranasal spray 15 minutes before laboratory simulated performance and social challenges (Visit 2). Those showing a predefined level of significant distress returned a week later (Visit 3) to receive, on a double-blind, randomly assigned basis, either intranasal PH94B (1.6µg) or placebo aerosol spray 15 minutes before repeat performance and social challenges.
Results: Patients receiving PH94B at Visit 3 had a significantly greater decrease in the mean Subjective Units of Distress Scores (SUDS) during the public speaking challenge and a trend toward lower SUDS scores during the social interaction challenge at Visit 3, as compared to Visit 2, than patients who had received placebo at both visits. PH94B also significantly exceeded placebo in percentage of patients much or very much improved (72% vs. 23%) when comparing the Visit 3 to the Visit 2 challenges.
Conclusion: These preliminary results suggest that PH94B might be an effective acute treatment for performance and social anxiety.
Disclosures/funding: Sponsored by Pherin Pharmaceuticals.
Lamotrigine for ketamine dependence: a randomized, double-blind, placebo-controlled trial
Presenters: Lin SK1, Huang MC1, and Chen CK2
Affiliations: 1Taipei City Hospital, Taipei, 2Chang Gung Memorial Hospital, Keelung, Taiwan
Background/Objective: Ketamine has become a popularly abused substance worldwide, including Taiwan in recent years, especially among the young and adolescent population. Lamotrigine is an anticonvulsant drug used in the treatment of epilepsy and bipolar disorder, with its main pharmacological mechanism being sodium channel blocking. It also inhibits the release of glutamate through modulation of high voltage-activated calcium currents and sodium channels. The aim of this clinical trial was to investigate the efficacy of lamotrigine in the treatment of ketamine dependence.
Design: After randomization, the dosage of study medication (25mg/day) was administered to subjects for seven days in a double-blind, placebo-controlled design. The dose was increased gradually to 100mg to 200mg/day by the end of 12 weeks. The primary end was negative result of urine screen between lamotrigine and placebo, and secondary ends were retention rate, subjective visual analogue scales (VAG) of craving, and clinical global impression of severity (CGI-S).
Results: In total, 17 subjects (lamotrigine: 9, placebo: 8) were enrolled in this trial. There was no difference in terms of demographics, history of substance use, and clinical severity. After treatment, no difference was found between the two groups, while a significant improvement was noticed within subjects in assessments of VAG and CGI-S.
Conclusion: Due to the small sample size, this trial did not find a better efficacy of lamotrigine in the treatment of ketamine use disorder, while a significant placebo effect was noticed.
Disclosures/funding: This study was registered in ClinicalTrial.gov (NCT02556060) and sponsored by Taipei City Government (10401-62-042). We thank Lotus pharmaceutical, Taiwan for sponsoring the trial drug and placebo.
PH94B nasal spray a PRN treatment for social anxiety disorder: a Phase 3 pilot trial
Presenters: Liebowitz MR1, Monti L2, Hanover R3, and Draine A1
Affiliations: 1Medical Research Network, New York, NY, 2Pherin Pharmaceuticals, Los Altos, CA, 3Westport Compass, Salt Lake City, UT
Background/Objective: Social anxiety disorder is a prevalent anxiety disorder that is often chronic and disabling. An effective rapidly acting pro re nata (PRN) treatment for social anxiety disorder could be highly useful.
Design: The study reported here was a Phase 3 pilot trial of PH94B, a synthetic neurosteroid delivered intranasally that acts via nasal chemosensory receptors to rapidly affect brain structures involved in anxiety. Subjects with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of social anxiety disorder carried a diary for two weeks, recording anxiety-producing social or performance events. Those who met predetermined criteria were randomized to two weeks of PH94B (1.6- and 3.2µg) or placebo, used PRN up to four times/day, followed by two weeks on the opposite treatment.
Results: Twenty-two subjects were included in efficacy assessments. PH94B was significantly more effective than placebo on the primary outcome measure, self-rated subjective units of distress (SUDS) scores of peak anxiety in feared situations, and, using between-subjects comparisons of the first two weeks of data, on several important secondary measures. Adverse effects were mild and did not show drug placebo differences.
Conclusion: If larger follow-up Phase III trials confirm our findings, PH94B could represent the first systematically studied PRN treatment for social anxiety disorder that could be used either as monotherapy or potentially as an adjunctive treatment.
Disclosures/funding: Sponsored by Pherin Pharmaceuticals.
A retrospective case-matched study of the efficacy of the MedicaSafe BupeCare device
Presenters: Mattai A
Affiliations: MedicaSafe, Inc.
Objectives: We sought to determine whether introducing a tracking and daily dispensing technology for medication-assisted maintenance treatment to patients with opioid use disorder would correlate with reduced illicit opioid use in the population.
Design: The dispenser was introduced to a portion of patients attending a clinic in White Plains, New York, who were diagnosed with opioid use disorder and stably maintained on buprenorphine treatment at least one point during their course of treatment. Paper records, including baseline assessment data, were maintained and reviewed for all patients. Urine and oral drug screening data were collected four months after the initiation of the cohort study.
Results: Due to a large spread of data points, each patient was given a score for illicit opioid use based on urine drug test results for every two weeks using their available data (a block analysis similar to the Treatment Effectiveness Score). The blocks were averaged across patients for each cohort (MedicaSafe vs. control). Results show that those patients on the dispenser had less opioid presence in urine than those in the control group. Subjects in the control group had an illicit opioid presence in urine of 33.3% at Weeks 8 to 16 of the study, and of 21.4% at Qeeks 16 to 24. Those in the MedicaSafe group had zero percent illicit opioid presence in those same weeks.
Conclusion: Use the MedicaSafe dispenser among patients in medication-assisted, opioid addiction treatment programs correlated with decreased presence of illicit opioids.
Scientific rationale and clinical development of AXS-05 for neuropsychiatric disorders
Presenters: O’Gorman C1, Jones A1, Kennon K1, Niecestro R1, and Tabuteau H1
Affiliations: 1Axsome Therapeutics, Inc. New York, New York, USA.
Background/Objective: AXS-05 is a novel, oral, investigational, fixed-dose combination of bupropion and dextromethorphan in clinical development for treatment-resistant depression (TRD) and agitation associated with dementia of the Alzheimer’s disease type. Bupropion serves to increase the bioavailability of dextromethorphan by inhibiting its metabolism through CYP2D6. Combined mechanisms of action of AXS-05 include NMDA-receptor antagonism, sigma-1 receptor agonism, and reuptake inhibition of norepinephrine, serotonin, and dopamine. The potential for pharmacokinetic and pharmacodynamic synergies with the combination exists.
Design: Phase I studies examined the pharmacokinetics of dextromethorphan after AXS-05 dosing. The efficacy and safety of AXS-05 is being evaluated in a Phase III, randomized, double-blind, active-controlled, 12-week study of subjects with TRD. This study consists of a six-week open-label, bupropion lead-in period, and a six-week, double-blind treatment period. The primary outcome measure is the Montgomery-Åsberg Depression Rating Scale (MADRS). The efficacy and safety of AXS-05 for the treatment of agitation in patients with Alzheimer’s disease is being evaluated in a Phase II/III randomized, double-blind, placebo-controlled, five-week study. The primary outcome measure is the Cohen-Mansfield Agitation Inventory (CMAI) score.
Results: In Phase I trials, co-administration of bupropion and dextromethorphan resulted in substantial increases in dextromethorphan plasma concentrations. AXS-05 was well tolerated. The TRD study (STRIDE-1) is expected to enroll approximately 350 subjects. The Alzheimer’s agitation study (ADVANCE) is expected to enroll approximately 435 subjects.
Conclusion: AXS-05 is a fixed-dose combination of dextromethorphan and bupropion. Increased dextromethorphan bioavailability has been demonstrated. Ongoing trials are evaluating AXS-05 in patients with TRD and in patients with agitation associated with Alzheimer’s disease.
Disclosures/funding: All authors are full-time employees of Axsome Therapeutics, Inc.
Tolperisone shows no evidence of sedation compared to cyclobenzaprine and placebo in a driving simulation study
Presenters: Caron J1, Kay G2, Rosenberg R3, Walling D4, Horonovich S2, and Hochadel T2
Affiliations: 1Neurana Pharmaceuticals, 2Cognitive Research Corporation, 3NeuroTrials Research, 4Collaborative Neuroscience Network
Background/Objective: Tolperisone is a centrally acting muscle relaxant being developed in the United States for treatment of occupational/sports-related muscle spasms. Tolperisone previously demonstrated muscle relaxant and analgesic effects without sedation. The present study explores the impact of tolperisone on driving, self-reported sleepiness, and cognition compared to placebo and cyclobenzaprine, an active comparator.
Design: This three-way, randomized, blinded, crossover study assessed the safety and effects on cognition of tolperisone in 36 healthy volunteers. Treatment groups included 450mg tolperisone administered three times a day (150mg TID), 30mg cyclobenzaprine (10mg TID), and placebo (TID). Participants spent three days a week for three weeks in the clinic. Dosing occurred on the morning of Days 1, 2, and 3, and in the afternoon (PM) and at bedtime on Days 1 and 2. Subjects completed 100km (60 minutes) of simulated driving on Day 1 one hour after their PM dose (i.e., at drug Tmax), and again the morning of Day 2 (pre-dosing) to assess next day residual effects, and the morning of Day 3 (post-dose) to assess the effects of drug accumulation seen at steady-state. Subjects returned on Days 7 and 14 to repeat procedures.
Results: For the primary endpoint of standard deviation of lateral position (SDLP) over 100km of driving, tolperisone was no different than placebo (p=0.9); cyclobenzaprine, however, showed significant impairment (p=<0.001). Additional measures of driving, self-reported sleepiness, cognition, and safety indicated no impairment for tolperisone versus placebo.
Conclusion: Tolperisone was found equivalent to placebo on measures of driving, self-reported sleepiness, and cognition, whereas cyclobenzaprine demonstrated significant impairment on SDLP, an objective measure highly correlated to blood alcohol levels.
Disclosures/funding: Judy Caron is an employee of Neurana Pharmaceuticals, the sponsor of this study; Russell Rosenberg is participating in a study funded by Neurana Pharmaceuticals; David Walling is participating in a study funded by Neurana Pharmaceuticals; Gary Kay and Thomas Hochadel are employees of Cognitive Research Corporation.
High frequency assessment of mood and cognition in major depressive disorder using the Apple iWatch
Presenters: Cormack F1,2, McCue M3, Schuster J3, Taptiklis N1,2, Glazer E1,4, Panagopoulos E1,4, Van Sheik T1,4, Fehnert B1,4, King J1,4, and Barnett JH1,2,5
Affiliations: 1Cognition Kit, Cambridge UK; 2Cambridge Cognition, Cambridge UK; 3Takeda Pharmaceuticals USA, Deerfield IL; 4CTRL Group, London UK; 5University of Cambridge Department of Psychiatry, Cambridge UK
Background/Objective: Patients with major depressive disorder (MDD) frequently experience cognitive problems, such as inattention and memory complaints. These are often under-recognized and might affect patients’ ability to accurately self-report symptoms. High frequency, near-patient testing might aid communication between patients and clinicians by overcoming challenges, such as recall bias. This study aimed to assess the feasibility, accuracy, and acceptability of daily assessments of cognition and mood implemented on an Apple iWatch in participants with MDD.
Design: Thirty participants between 18 and 65 years of age with mild-to-moderate single or recurrent major depressive episode prescribed antidepressant monotherapy were enrolled. Brief cognitive and mood tests were administered daily through the Cognition Kit application on Apple iWatch in a single-arm, unblinded, six-week observational study. Performance was measured on Cambridge Neuropsychological Test Automated Battery (CANTAB) cognitive function tests and patient-reported measures of depression symptom severity, social function, and perceived cognitive difficulties on four occasions. At the first and final visit, a semi-structured interview was carried out to assess subjective motivation and barriers to adherence.
Results: Participants showed excellent adherence with daily testing of both mood (95%) and cognition (96%). Abbreviated daily assessments delivered through this wearable device showed good correspondence with full-length patient reported outcomes and objective CANTAB cognitive tests.
Conclusion: Near-patient testing using wearable devices is feasible and well-tolerated by patients with depression. Good correspondence with patient reported outcomes and objective measure was shown, providing a novel, patient-centric methodology for frequent assessment of a range of symptoms.
Disclosures/funding: Project funded by Takeda Pharmaceuticals USA.
Patient engagement text messaging reduces drug interruption and patient dropout in Phase III bipolar depression clinical trial
Presenters: Curtin D, Johnson M, Putnam T, and Griffin A
Affiliations: mProve Health, LLC, QuintilesIMS
Background/Objective: We aimed to define the impact of patient engagement text messages for patients participating in a bipolar depression clinical trial, and to evaluate patients’ protocol adherence and dropout rate.
Design: In an ongoing Phase III, double-blind, safety and efficacy study for patients with bipolar depression, study-related text messages were offered to patients. These messages included daily medication reminders, study visit reminders, and appreciation messages to alert patients of protocol obligations. Participating research sites were given the option of offering these communications to patients, thereby creating comparators of patients, one receiving communications and second comparator that did not. The impact of receiving study communications was assessed across the two patient comparators using two measures: drug interruption and study discontinuation.
Results: The average number of drug interruption protocol deviations for patients receiving communications versus patients not receiving communications were 0.03 and 0.26, respectively, for an 85-percent reduced risk in drug interruption (p=0.05). Trial sites who offered study communications to patients had 250-percent fewer patient withdrawals than sites who did not offer communications.
Conclusion: Employing text message reminders to support patients in completing protocol obligations, such as dosing and scheduled visits, consistently demonstrate positive effects on protocol deviations and retention. Supportive communications encourage adherence to time-sensitive medication dosing in addition to enabling patient engagement through study completion, thereby limiting the need for further recruitment and enrollment costs.
Presenters: Hendry P, Armstrong K, Barag J, and Kramer L
Background/Objective: The STARR Coalition is a nonprofit organization consisting of thought leaders throughout the pharmaceutical industry, CROs, clinical research sites, and advocacy. Our mission is to build unbiased, collaborative initiatives to reduce the stigma associated with CNS disorders and promote research as an option for those seeking help. A strong link exists between mental illness and suicide. Are opportunities available for clinical research in psychiatric disorders to make a difference?
Up to 20 percent of individuals with a diagnosis of mental illness complete suicide. Ninety percent of those who complete suicide experience mental illness. People considering suicide usually seek help: 64 percent who attempt suicide visit a doctor a month before their attempt. Having a chronic condition increases the odds of suicide by 363 percent. This poster reviews the need to integrate suicide prevention education and support into clinical research’s processes and culture. What currently happens when a person with suicidal thoughts calls a research site?
Design: “STARR911” is a concept to build collaboration between clinical research and suicide prevention. Clinical research call centers field thousands of calls on a yearly basis. During first contact, operators are trained on best practices to recognize callers who might have suicidal ideation. Options might include educational information, de-escalation techniques, and access to “warm” handoffs to suicide prevention specialists. The concept can be adopted for all indications, but we see the immediate need for those within the CNS realm.
Results: Assessing the outcome measures will begin with tracking multiple areas: 1) creating a designated “warm” line for call centers and sites to transfer individuals with potential suicidal ideations. The number of calls can be tracked and calculated; and 2) Call centers and sites can also complete a suicide assessment questionnaire, which can be tracked and calculated. STARR911 can do periotic follow ups and receive feedback from call center operators and sites.
Conclusion: Research can be a part of the solution to suicide prevention. Progressive initiatives are key for re-search to be considered a part of the healthcare community and to gain credibility for drug development.
Validity and retest-reliability of sleep measurements using a simple, self-applicable device
Presenters: Dorffner G1,2, Gruber G1, Parapatics S1, Loretz E1, Kemethofer M1, Simeoni M2, Rainer L2
Affiliations: 1The Siesta Group; 2Medical University of Vienna, Section for Artificial Intelligence and Decision Support, Vienna, Austria
Background/Objective: Portable solutions for sleep measurement (polysomnography [PSG]) in clinical trials are gaining interest. However, most such solutions still require involvement of highly skilled personnel, thus limiting the potential scope of those instruments. Recently, we presented a new method of sleep staging based on a reduced setting using only two electrooculography (EOG) channels. The aim of this prospective study was to explore further the reliability and validity of this reduction.
Design: Twenty healthy subjects (aged 20–29 years) participated in the study. A reduced recording setup was used for five consecutive nights using an Actiwave miniature recorder (Camntech, Cambridge UK). During the first night, a full PSG according to standard criteria was recorded simultaneously. All 120 recordings were analyzed, either using a validated computer-assisted scoring system for the standard PSGs or a modified version adapted for the reduced two-channel setup.
Results: Data loss was minimal in the two-channel recorder. The number of epochs not scoreable was 1.3 percent in the portable device. In general, the differences of target variables between reduced and standard setup were marginal in absolute terms: Sleep efficiency: -0.47 percent (SD=2.6), Wake after Sleep Onset: -3.2 minutes (SD= 9.05), Percentage of stage N1: – 0.24 percent (SD=4.57), N2: -0.61 percent (SD=7.36), N3: -0.52 percent (SD=7.17), and R: +1.44 (SD=4.5). No significant differences were found in a paired samples t-test in any variable. All sleep parameters turned out to be very stable during the five nights. Analysis of variance (ANOVA) for repeated measurements as well as Kruskal-Wallis H-tests did not reveal any significant differences in any variable. Effect sizes of internight differences evaluated by Cohen’s d were below 0.2 (very small to no effect) for the vast majority of pairwise comparisons.
Conclusion: The results provide further evidence that, with appropriate computer-supported sleep scoring, data obtained by means of a two-channel portable device lead to sleep measurements similar to a full PSG.
Disclosures/funding: Georg Dorffner is an employee and shareholder of The Siesta Group GmbH.
Patient Assessment and Adherence
Criteria satisfied on diagnostic instrument often not confirmed on severity ratings
Presenters: Sachs G, Reksoprodjo P, Roy M, Kott K, and Busner J
Affiliations: Bracket Global
Background/Objective: Entry criteria for randomized, acute depression studies typically include both a categorical requirement (meeting Diagnostic and Statistical Manual of Mental Disorders [DSM] criteria for major depressive episode [MDE]) and a threshold score on a continuous severity measure. When these distinct assessment techniques produce incongruent results, the diagnosis might be unreliable. We interrogated blinded data sets from recent acute depressions studies to determine the frequency of this potential unreliable diagnosis.
Design: Data from eight double-blind, randomized acute major depressive disorder (MDD) studies were analyzed. We considered Montgomery-Asberg Depression Scale (MADRS) items clinically significant if for scores of 4 or higher. Subjects were classified as Insufficient Gating Criteria if three MADRS items—Apparent Sadness, Reported Sadness and Inability to Feel—were all rated below the clinically significant range, and as Insufficient Pychopathology for MDE if the corresponding MADRS items fewer than four DSM criteria were rated 4 or higher. Unreliable diagnosis was defined as meeting DSM criteria by a diagnostic instrument but lacking gating criteria or having insufficient psychopathology for a MDE diagnosis.
Results: Among 3,256 subjects with screening and baseline assessments, 3,091 (95%) were randomized. Of these, 667 (21.6%) met operational criteria for unreliable diagnosis, 124 (4%) lacked gating criteria n=124 (4%), and 660 (21.4%) had insufficient psychopathology for MDE. The proportion of unreliable diagnosis varied widely across studies (9.2–37.7% (c2(8)=153.5;p<0.001).
Conclusion: Our analysis found high rates of unreliable diagnostic assessment, and supports the use of diagnostic validation procedures in clinical trials. Further analysis will assess signal detection these subjects.
Data quality concerns associated with PANSS negative items: an exploratory analysis
Presenters: Kott A, Daniel DG
Affiliations: Bracket Global, LLC
Background/Objective: Within the Positive and Negative Syndrome Scale (PANSS), errors are frequent and are associated with increased response to placebo. Most of the currently available data checks focus on positive and some general psychopathology items. We have recently developed a battery of data quality checks identifying discrepancies associated with negative items of the PANSS. In the current analysis, we explore this battery in a database of 17 schizophrenia clinical trials.
Design: Data from 17 Phase II and III double-blind, placebo-controlled, multicenter schizophrenia trials were analyzed. Each visit was tested for the presence of errors associated with the negative items. Using logistic and negative binomial regression we assessed the association between the presence of these errors in the screening and post-baseline periods.
Results: The dataset consisted of 73,115 visits administered across 11,487 subjects. Errors associated with negative symptoms were identified in nearly 15 percent of visits in acute schizophrenia studies and in more than 22 percent of visits in studies with predominantly negative symptoms. The presence of the errors in the screening period was associated with 8.4-times increased odds and with a 328-percent increased incidence of recording the same errors after baseline.
Conclusion: We have developed a battery of data quality checks focusing on errors associated with PANSS negative items. The presence of these errors in the screening period was highly associated with their reoccurrence after baseline. Intelligent eCOA and data-analytic approaches should be used to screen for these errors and trigger subsequent remedial intervention, preferably before subject’s randomization.
Disclosures/funding: Both authors are full-time employees of Bracket.
Effect of predominance of negative symptoms at baseline on change in the PANSS total in acute schizophrenia trials—an exploratory analysis
Presenters: Kott A, Daniel DG
Affiliations: Bracket Global, LLC
Background/Objective: We aimed to evaluate the effect of predominance of negative symptoms over positive symptoms on change from baseline to last visit in acute schizophrenia trials.
Design: Blinded data were analyzed for 6,700 subjects in 10 double-blind, placebo-controlled studies of acutely ill subjects with schizophrenia. Based on baseline scores on the Positive and Negative Syndrome Scale (PANSS) negative subscale score and the PANSS positive subscale, the sample was dichotomized into two groups: subjects with more severe positive symptoms than negative symptoms and subjects with more severe negative than positive symptoms. At the end of treatment, we compared the change in the PANSS total score between the two groups within each protocol using a two-sided t-test.
Results: Among the 10 studies, at baseline the severity of negative symptoms exceeded the severity in positive symptoms in 32 to 46 percent of subjects, mean=38.2 percent (SE=0.8). Differences among the studies in the proportion of predominantly negative symptom and predominantly positive symptom subjects at baseline were statistically significant (c2(9)=27.4, p<0.01). We identified no differences between the magnitude of the PANSS total change from baseline to end of treatment by negative or positive symptom predominance in nine out of the 10 analyzed studies. In one study, the mean change in the group with more severe negative symptoms was significantly different (indicating greater improvement) from the group with more severe positive symptoms (-21.8±19.1 vs. -17.7±18.8; t(424)=2.18, p<0.05).
Conclusion: Our data suggest that more severe negative than positive symptoms at baseline usually do not reduce change at end of treatment compared to subjects with more severe positive than negative symptoms. The current exploratory data analysis is blinded to treatment status and thus does not address the effects of the ratio of negative to positive symptoms at baseline on placebo-drug differences. This question will be addressed in future analyses.
Real-world patient experience with treatment-emergent sexual dysfunction in depression
Presenters: Jacobsen J1, Thorley EM2, Curran C2, and Chiauzzi E2
Affiliations: 1Takeda Development Center Americas Inc., 2PatientsLikeMe, Inc.
Objectives: Despite the prevalence of treatment-emergent sexual dysfunction (TESD) in antidepressant treatment, little is known about patients’ related real-world experiences.
Design: A cross-sectional survey (N=483) was developed and fielded to members from PatientsLikeMe, an online data-driven patient network self reporting major depressive disorder (MDD). Sexual functioning was assessed using the Changes in Sexual Functioning Questionnaire-short form (CSFQ-14) and a patient attribution question. Survey measures also included the Patient Health Questionnaire Depression Scale (PHQ-8), and the Couples Satisfaction Index-4 (CSI-4).
Results: Based on CSFQ scores, 56 percent of the participants taking antidepressants reported sexual dysfunction. Sexual dysfunction was associated with depression severity for both women and men and was associated with lower relationship satisfaction (CSI-4) among women currently taking antidepressants. Based on patient attribution, less than half with TESD mentioned it to their doctor, and a minority (ranging 20–36%) indicated that their doctor subsequently switched them to another antidepressant. In response to issues with sexual functioning, 48 percent stated they continued taking their current antidepressant(s) until sexual side effects went away; 36 percent adjusted their dosing (lower dose, skipped dose); and 11 percent indicated taking another medication to improve sexual functioning.
Conclusion: Sexual dysfunction is associated with greater depression severity and relationship dissatisfaction. Despite various actions taken by patients to ameliorate sexual dysfunction, over half currently taking antidepressants were still experiencing TESD.
Disclosures/funding: Paula Jacobsen is an employee of Takeda Development Center Americas Inc. This study was funded by Takeda Pharmaceuticals U.S.A., Inc.
The SAGE-SR: item development and initial validation of a DSM-5 and SCID-based self-report diagnostic assessment.
Presenters: Brodey BB, Zweede EA
Affiliations: TeleSage, Inc., 201 E. Rosemary St., Chapel Hill, NC 27514 USA
Background/Objective: Our objective was to develop and validate a rigorous self-report diagnostic assessment based on DSM-5 and ICD-10 diagnostic criteria that can be used to accurately identify any of 31 standard behavioral health diagnoses and to facilitate screening people for eligibility to participate in FDA clinical trials.
Design: The item development and validation process included an expert panel, four clinical sites, and a control population. An expert panel iteratively developed items based on the exact individual symptoms, time-frames, and clustering described in the DSM-5 and the Structured Clinical Interview for DSM-5 Disorders (SCID-5). Items were tested using cognitive interviewing (CI) with a total of 50 participants in three rounds. Items that gave rise to any confusion were re-written and re-tested iteratively with CI until all items were clearly understood in the final round of CI. Items were placed into a computer adaptive instrument in sequential order based on the SCID-5, and a branching pattern was developed to eliminate non-contributory items during each assessment. The resulting SAGE-SR was administered to 44 public sector clinical participants and to 84 nonclinical controls.
Results: We successfully developed and validated 661 items covering the exact symptoms, time frames, and clustering criteria for the 31 most common DSM-5 diagnoses. The resulting computer adaptive program ran smoothly and was well liked by study participants. A clinical report was successfully generated after each assessment. The assessment took 14 minutes (SD=6.8) and 24 minutes (SD=12.5) to administer to clinical controls and public sector participants respectively.
Conclusion: The SAGE-SR is a brief self-report diagnostic assessment that can be used to efficiently screen large populations in order to identify individuals who might be appropriate for participation in specific clinical trials. The SAGE-SR also provides a detailed exportable symptom database that can be used to identify sub-populations that have a robust response to a clinical intervention.
Disclosures/funding: This research was supported in part by a grant from the National Institutes of Mental Health, which was awarded to TeleSage, Inc. Dr. Brodey is Chief Executive Officer of TeleSage, Inc., and Dr. Zweede is employed by the company as a clinical research specialist.
Subjects’ knowledge of symptoms that can occur during seizures
Presenters: Ly JJ, Yamamoto RT, Khurana L, Gerzon M, Dias NR, Durand EM, Gary ST, Tuller JM, and Dallabrida SM
Affiliations: ERT, Boston, MA
Background/Objective: The aim of this study was to assess subjects’ knowledge and recognition of common symptoms that can occur during various types of generalized and partial focal seizures.
Design: Participants (N=645) completed an online survey asking them to endorse, in a checklist format, 10 common symptoms that can happen during seizures. All participants reported that they did not have a history of seizures. Demographic information were also recorded.
Results: Most participants endorsed symptoms associated with clonic-tonic seizures including loss of consciousness and falling to the ground while shaking on both sides of the body (82% and 91%, respectively) as symptoms that can occur during seizures. Fewer participants identified symptoms associated with tonic (muscles become tense or rigid, 78%), clonic (twitching in one arm or leg, 72%), absence (staring into space, 65%; rapid eye blink, 61%; eyes rolling back, 86%), and atonic seizures (muscles become weak or limp, 54%). Many of the respondents did not endorse symptoms associated with complex partial (repeated movements like clapping, lip-smacking, or walking, 44%) and simple partial seizures (change in how things look, smell, feel, taste, or sound, 51%).
Conclusion: Clinical trials for epilepsy often involve seizure frequency as a primary endpoint. Findings have shown that caregivers often underreport seizure frequency. Our results suggest that caregivers might have difficulty identifying many symptoms that can occur during seizures, especially partial focal and atonic seizures. Training caregivers might be beneficial in improving the accuracy of seizure frequency.
Disclosures/funding: All authors are employees of ERT.
Training, above all other motivators, is preferred by subjects with CNS disorders for motivating them to complete daily questionnaires
Presenters: Yamamoto RT, Ly JJ, Dias N, Durand EM, Gary ST, Gerzon M, Khurana L, Tuller JM, and Dallabrida SM
Affiliations: eResearch Technology
Background/Objective: We aimed to determine what would most motivate clinical trial subjects with CNS-related diagnoses to complete daily questionnaires, as well as how much time they would be willing to commit to training.
Design: There were 273 patients (26% of which had previously participated in a clinical trial) with at least one CNS-related diagnosis who responded to an online survey. Respondents were 18 to 79 years old (74% female). In addition to demographics and diagnoses, patients reported what would most motivate them to complete study questionnaires on a daily basis and, if they were provided educational information in a clinical trial, how much time would they be willing to spend training.
Results: Fifty-six percent of those respondents who had previously participated in a clinical trial and 64% of those who had not previously participated in a clinical trial reported that they would be motivated by training, selecting either A) “If I were trained on the importance of my role and what to expect in the study,” (B) If I were trained about the purpose and importance of the questionnaires, or both (A) and (B). Of respondents motivated by training, 33 percent were willing to spend an hour or more training, and 34 percent said they’d spend 30 to 60 minutes training. For respondents motivated by other things, 24 percent would be willing to spend more than an hour training, and 32 percent said they’d spend 30 to 60 minutes training.
Conclusion: Training was the number one factor chosen by respondents to motivate them to complete daily questionnaires, surpassing reminders, money, games, or any other motivators. Training motivates subjects to be adherent with daily diary completion in clinical trials, and these subjects are willing to spend time to be trained.
How to scale up recruitment in Alzheimer’s disease clinical trials from 3 to 100 screens a month
Presenters: Cajal M and Stanton S
Affiliations: Bioclinica Research Network, formerly Compass Research, Orlando, FL, USA
Background/Objective: With so many Alzheimer’s disease (AD) and AD prevention clinical trials and numerous patients affected, sites need to scale up their recruitment from three screens a month to 100 screens a month consistently.
Design: We combined a variety of recruitment approaches to assess which ones were most effective at generating high recruitment volumes. Recruitment approaches tested included use of digital media (Facebook, Studykik, Clinical Connection, and Trial Spark); print; TV; radio ads; direct outreach to patient database via mail, email or phone; physician partnerships; and community outreach.
Results: Over four months of using those recruitment strategies in combinations, the results were as follow: 38 percent of screened patients originated from physicians’ referrals, either from the investigator’s private practice or from colleagues in Central Florida working with our community liaisons. Twenty-one percent came from direct community outreach (especially from physician’s educational seminars), participation in health fairs, and caregiver support groups. Twenty-one percent came from engaging our own database of previous participants as well as subjects having expressed interest in the past. Lastly, 20 percent originated from more traditional marketing (i.e., print, radio, TV, and the use of digital media).
Conclusion: In order to significantly scale up recruitment in AD studies, no patient engagement method should be neglected. Efforts should be made to provide information to the community as a whole, including patients, caregivers, and physicians, in order to raise awareness of AD and clinical trials. In the end, a volunteer’s participation is directly linked to their understanding of clinical trials.
Disclosures/funding: The authors are employees of Bioclinica Research Network, formerly Compass Research.
Patient recruitment campaign strategies and effectiveness in a clinical trial of patients with opioid use disorder
Presenters: Ramos J1, Miller M2, Carter D1, Farfel L1, and Martin W1
Affiliations: 1Alkermes, Inc. and 2StudyKIK
Objectives: Our aim is to present the results of a patient recruitment campaign (PRC) as well as methodologies utilized to recruit patients in a challenging trial of patients with opioid use disorder (OUD).
Background: ALK6428-A301 was a Phase III study to evaluate the efficacy, safety, and tolerability of low doses of oral naltrexone used in conjunction with sublingual buprenorphine (BUP) for adults with opioid use disorder (OUD) prior to the first injection of VIVITROL® (naltrexone for extended-release injectable suspension). Recruitment of patients with OUD is a challenging and complex endeavor in a clinical trial setting. Additionally, concern of receiving placebo is often a major deterrent for clinical trial participation in this patient population. A unique challenge of this trial was a statistical requirement of a representative balance of patients currently using heroin or prescription (Rx) opioids. Given these factors, the present trial required the implementation of a recruitment strategy uniquely tailored to this patient population to ensure enrollment targets were met.
Design: This 16-week trial required that the population (n=380) comprise approximately 65-percent heroin users and 35-percent Rx users. The trial consisted of three treatment arms that contained ascending oral naltrexone (or placebo) and descending BUP (or placebo). All subjects received an ancillary medication regimen as part of a seven-day outpatient detoxification with VIVITROL administration on Day 8. The recruitment strategy included a comprehensive PRC incorporating traditional advertising tactics (e.g., print, TV, and radio), and digital campaign (e.g., banner ads, Pandora, and StudyKik). A branded component of the PRC, “Crossroads,” focused on Rx patients at risk for transitioning to heroin.
Results: Of the 657 patients screened for trial participation, 505 (77%) were recruited from advertising and 264 of 380 (70%) randomized came from advertising. Approximately 60 percent of randomized heroin users and 80 percent of randomized Rx users came from advertising. Over the final four months of the trial, approximately 80 percent of randomizations came from PRC tactics. It is estimated that without the PRC, this trial would have taken an additional four years to enroll, while costing more than twice as much. Overall, no differences were noted in primary endpoint with regard to the patient source, i.e., coming from the PRC vs. non-PRC.
Conclusion: The patient recruitment campaign implemented in the present trial of patients with OUD was effective and resulted in cost and time savings. No apparent differences were observed in key quality metrics of patients recruited from advertising vs. non-advertising sources. Patient recruitment campaigns in this patient population might be an effective way to reduce clinical trial time and cost without sacrificing the integrity of the trial data.
Disclosures/funding: ALK6428-A301 was an Alkermes-sponsored clinical trial. Jandira Ramos, Denise Carter, Laura Farfel and William Martin are currently employed by Alkermes.
Patient selection for CNS clinical trials: findings from an eligibility review database with a focus on Alzheimer disease trials
Presenters: Hilsabeck RC, Murphy J, Yakovleva N, Reinhold CK, Miloslavich K, and Nations KR
Affiliations: INC Research/inVentiv Health
Background/Objective: The purpose of this analysis was to examine key areas of vulnerability in patient selection for CNS trials and specifically in Alzheimer’s disease (AD) trials.
Design: A contract research organization (CRO)-based team of physicians and clinical scientists reviewed key screening diagnostic and medical data prior to subject randomization. Resulting eligibility concerns were thereafter discussed with sites, leaving final decisions on randomization in the hands of investigators.
Results: A total of 29,266 patients, all submitted by investigators as qualified, were reviewed in 36 trials (psychiatry, neurology, and analgesia). Of these, 2,605 (9%) were not eligible to randomize. Despite significant variability between indications (range 4.8–16.1%), findings did not significantly differ between general therapeutic areas (x2(2)=3.10, p=0.212). In AD trials, 16.1 percent of patients were considered unsuitable for participation, which is significantly higher than all other indications combined (x2(1)=56.54, p<0.001). Reasons AD patients were considered ineligible were broad, including, but not limited to cardiovascular disease risk (22%) and dementia not due to probable AD (20%). Additional data, including regional differences and most common findings, are presented.
Conclusion: This analysis demonstrates that CNS trials are susceptible to penetration by unqualified/unsuitable patients, and that AD trials are among the most vulnerable. High rates of AD patient selection error, 85 percent higher than the rate for all other indications combined, might shed some light on how protocol and patient complexity increases risk, and ways in which trial designers and managers can focus their efforts to protect trial quality and patient safety.
Disclosures/funding: All authors are employees of INC Research/inVentiv Health, the Contract Research Organization responsible for execution of all trials included in this analysis.
You show me your (I/E) and I’ll show you my (diagnosis): professional subjects changing indications
Presenters: Shiovitz TM1,2, Steinmetz CB1, Fox BL1, Rickers SL2, and Schoneberg SH1
Affiliations: 1CTSdatabase LLC, Sherman Oaks, CA; 2California Neuroscience Research, Sherman Oaks, CA
Background/Objective: Professional subjects are individuals who participate in multiple, and often concurrent, studies in order to collect stipends. They might change their presentation to satisfy inclusion or exclusion criteria of each study. Professional subjects are a substantial problem in clinical trials and might contribute to study failure. We seek to understand how professional subjects might change their indications/diagnoses in order to qualify for disparate studies.
Design: We performed a search of matching subjects in CTSdatabase on August 11, 2017. Subject data was sorted to determine how frequently there was a change in prescreening indication or screening diagnosis. Only matches that occurred at unique sites were included in the data set.
Results: Of 11,969 matches that have occurred since subjects were first entered in October 2011, 16.1 percent (1,925) involved a change of indication or diagnosis between sites. The most frequent cross-indication pairs were schizophrenia and depression (3.06%), schizophrenia and bipolar (1.96%), depression and bipolar (1.62%).
Conclusion: Professional subjects participate in multiple studies and might change their presentation when appearing at different sites. This might be unintentional or purposefully deceptive. Changing indications might be appropriate, such as depression co-occurring with anxiety or migraine, or inappropriate, such as participating in an opioid-induced constipation study concurrently with a study of opioid augmentation of treatment-resistant depression. In any case, multiple changes of diagnosis or indication should raise the suspicion of a professional subject.
Disclosures/funding: A subject registry, such as CTSdatabase, can detect these subjects and provide a history of previous study participation, including screening diagnoses.
Mitigating placebo response in CNS clinical trials: a site based pilot program
Presenters: Tireman E, Templeton K, and Kakar R
Affiliations: All authors are from Segal Trials in Fort Lauderdale, Florida
Background/Objective: It is a widely known that just receiving treatment can improve a patient’s symptoms. Due to this phenomenon, a majority of clinical trials are randomized and have a placebo arm. The placebo effect is a response to this inactive treatment arm; however, it is not only just a response to the treatment itself, but also rather a response to the entire experience. It is well known among the CNS drug development scientists that the placebo effect is a significant hindrance to the progression of new drug development. There are many factors that combine to create this placebo effect. The receiving of treatment of any kind, whether it is the investigational product or intervention or placebo, is just the start of it. Things such as psychosocial factors, expectations, and even how the placebo is administered have all been shown to be factors in response. The major problem with the placebo effect is that the bigger the placebo response, the harder it is to show that an experimental treatment is effective. This leads to an overwhelming number of failed clinical trials, wasted money by the pharmaceutical companies, and a large number of drugs that are abandoned due to the failed response rates. A large percentage of antidepressant and antipsychotic drug trials have failed due to increased placebo response. This is often due to the reliance on patient-reported outcomes and subjective/objective assessments for the efficacy measures. There are many psychosocial and expectancy factors that might also affect the outcomes of these trials. The increasing occurrence of placebo response among CNS trials is leading to less funding for CNS research, an area that is still in need of new medications for additional indications or insufficient symptom relief. As a consortium of sites, our goal is to develop a site-based program, targeting CNS trials, to mitigate the elevated placebo response.
Design: We are seeking to develop material for staff training and patient education targeting minimizing placebo response in CNS clinical trials; provide detailed training to all staff for detailed understanding of protocols and endpoints so they are able to focus on obtaining accurate and unbiased data; develop patient education materials differentiating research and treatment relationships, clinical trial expectations, double-blind, and placebo; and collaborate with pharmaceutical companies to pilot this program using their clinical trials and obtain site specific outcome data to compare program efficacy.
Financial disclosure/funding: None reported.
The power of an educational placebo response video: strengthening subject placebo response awareness across demographic variables and diagnoses
Presenters: Hassman H, Cohen EA, Myers K, Hossain SI, Joseph AV, and Lobb J.
Affiliations: Hassman Research Institute Science Division
Introduction: The clinical trial industry continues to grapple with increasing placebo responses. One technique that merits empirical exploration is educating subjects on factors linked to their potential increased response to the ‘inert’ substance. These factors include site-subject interactions, subject expectations, lack of subject understanding of the placebo, and subject role uncertainty. Our study investigated whether an educational video would raise subjects’ awareness about these factors across age, sex, and diagnostic indication, ultimately leading to reducing subjects’ response to the placebo.
Methods: Patients with a CNS, addiction, or general medicine diagnoses completed a Placebo Awareness Questionnaire (PAQ) to assess awareness of the placebo response key factors. Upon completion of the PAQ, subjects were randomized to the Intervention Group (IG; n=100) where they watched a seven-minute video regarding these factors and completed a post-PAQ. Control group subjects (CG; n=100) completed the PAQ without watching the video.
Results: A repeated measures analysis of variance (ANOVA) showed a significant difference between the IG and CG groups such that the IG subjects were better able to identify the placebo response factors after watching the video (p<0.001). Secondary analysis indicated this finding was true across age, sex, and diagnoses (all p<0.05 except for the 20–29 year age group).
Conclusion: Within-group analyses suggests a differential effect of the intervention on the subgroups (e.g., IG women scored higher than IG men post-video). Implications are discussed.
Disclosures/funding: All authors are full-time employees of Hassman Research Institute and have no conflicts of interest for this work.
Rater Training and Assessment
Distribution of performance and incorrect ratings in qualification video scoring
Presenters: Enger B, Barbone JM, and Eckart C
Background/Objective: We aimed to answer the methodological question: Do rater training programs utilizing the standard qualification video scoring error remediation process sufficiently contribute to the goal of maximizing rater calibration prior to the start of a study?
Introduction: A long-held standard in the CNS Clinical Trial Rater Training industry is that in order to successfully complete video qualification scoring and be qualified to rate in a study, raters must score 80 percent of the scale items within an acceptable score range set by the consensus of an expert scoring panel. Raters scoring 80 to 99 percent on qualification scoring typically receive no remediation. Raters scoring 60–80 percent are provided a remediation of each item scored out of range, including re-training on the proper scoring for each of the items scored out of range, and are often asked to rescore the video. Raters scoring below 60 percent are neither recommended to rate in the study nor remediated and are not included in this analysis.
Design: Rater scoring data from Bracket’s rater database across 25 protocols were analyzed for the number of scoring errors on study qualification videos for the Positive and Negative Syndrome Scale (PANSS), Montgomery-Asberg Depression Scale (MADRS), and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-Cog).
Results: For the cohort of trained and qualified raters who went on to administer the scale, the following percentage of qualification scoring errors were not remediated: 61 percent for PANSS, 54 percent for MADRS, and 70 percent for ADAS-Cog.
Conclusion: This represents a significant missed opportunity to improve scoring precision at a critical time in the study, prior to the assessment of the first subject. A 100-percent remediation approach would take advantage of this opportunity and could improve rater performance via endpoint reliability findings.
Disclosures: This poster was funded solely by Bracket Global, LLC.
Identification of Children’s Depression Rating Scale—Revised (CDRS-R) items of particular challenge to raters in child and adolescent depression clinical trials outside of the United States
Presenters: Busner J1, Findling RL2, and Robb A3
Affiliations: 1Bracket; 2Johns Hopkins Medicine, Department of Psychiatry, 3Children’s National Medical Center, Department of Psychology and Behavioral Health
Background/Objective: For the gold-standard pediatric depression scale, the Children’s Depress Rating Scale (CDRS-R), we previously identified items of particular ratings to be challenging for US raters by detecting items of highest interrater variability. In the present study, we sought to identify such items, if present, in a non-US multi-trial international sample.
Design: The analysis included 984 ratings of four standardized, paired patient/parent videos scored by investigators from 23 countries for multiply-sponsored trials. Per-country, per-item standard deviations (SDs) for each of the 17 CDRS-R scored items were computed for each video, eliminating the two country ratings that contained less than five raters. Item SDs were ranked by order representing least to most scoring variability. Ranks were assessed for cross-country and cross video agreement using Kendall W.
Results: Within each video, cross-country agreement of SD rankings was statistically significant (P<0.0001). Collapsed across country, cross-video agreement of SD rankings was statistically significant (p<0.0002). Three high-SD items were among the top five for at least three of the four videos: Physical Complaints (PC), Low Self-Esteem (SE), and Hypoactivity (H).
Conclusion: Items with high variance potentially harm signal detection. Two of the three high-SD items in this international sample (LSE and H) were also identified in the US analyses, suggesting the need for better standardization of conventions across countries. The new PC finding might reflect a need for nuanced cultural conventions for interpreting somatic illness expression. Overall, the findings can be used to inform training, remediation, and other scale guidance interventions in child and adolescent depression trials.
Disclosures: J. Busner is a full-time employee of Bracket. In the past 12 months, R. L. Findling: In the past 12 months, Dr. Findling receives or has received research support, acted as a consultant, and/or served on a speaker’s bureau for Akili, Alcobra, Amerex, American Academy of Child & Adolescent Psychiatry, American Psychiatric Press, Bracket, Epharma Solutions, Forest, Genentech, Ironshore, KemPharm, Lundbeck, Medgenics, NIH, Neurim, Otsuka, PCORI, Pfizer, Physicians Postgraduate Press, Roche, Sage, Shire, Sunovion, Supernus Pharmaceuticals, Syneurx, Takeda, Teva, TouchPoint, Tris, and Validus. A. Robb receives or has received research or travel support, acted as a consultant, served on a speaker’s bureau, or owns stock or equity in American Academy of Child and Adolescent Psychiatry, American Academy of Pediatrics, Bracket, Eli Lilly, Actavis/Allergan/Forest, GlaxoSmithKline, Johnson & Johnson Ser-vices, Lundbeck, NICHD, Otsuka, Pfizer, SyneuRX, Sunovion. She serves on the Advisory Board for Aevi Genomic Medicine, Neuronetics, NICHD EKS, NIMH, University of Cambridge; NCATS, NINDS, Pfizer, Inc., Supernus. She receives royalties from Guilford Press.
A retrospective analysis of the effects of protocol design on completion rates in outpatient clinical trials in subjects with schizophrenia or schizoaffective disorder
Presenters: Krefetz DG and Kazmi S
Affiliations: PRA Health Sciences, Early Development Services, Marlton, NJ
Background/Objective: We sought to identify protocol design variables that are associated with improved study completion rates in outpatient clinical trials in subjects with schizophrenia or schizoaffective disorder.
Design: The authors previously conducted a retrospective analysis of the effects of protocol design on completion rates in Phase I inpatient studies with subjects with schizophrenia or schizoaffective disorder. The authors now study the impact of protocol design on study completion in outpatient clinical trials in subjects with schizophrenia or schizoaffective disorder. The authors examined the effect of 11 protocol design independent variables on completion rates in 58 outpatient clinical trials with subjects with stable schizophrenia or schizoaffective disorder. These trials were conducted at three clinical trial sites from 2006 to 2016. The sites enrolled 715 subjects in these trials. The variables studied include length of study, longest period between visits, number of visits, whether subject remained on pre-study antipsychotic, presence of a placebo arm, administration route of the investigational product, length of psychiatric stability required at screen, length of time since last trial participation required, whether the trial included subjects with schizoaffective disorder, phase of study, and the primary aim of the trial (safety, general efficacy, relapse prevention, negative symptom efficacy, or cognitive impairment efficacy). Variables were 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 is presented.
Conclusion: Conclusions can be drawn that inform study design for better subject retention.
Disclosures/funding: Nothing to disclose
Toward more efficient methods for COA instrument selection in clinical trials
Presenters: Zaragoza Domingo S1 and Bishop K2
Affiliations: 1Neuropsychological Research Organization s.l., Barcelona, Catalonia, Spain, 2Global Pharma Consultancy, USA
Background/Objective: To innovate on clinical outcome assessments (COAs) and COA instrument selection by introducing the concept of efficacy-based selection. With this objective, a theoretical framework for existing initiatives is presented.
Rationale: There is an urgent need in cognitive neuroscience to improve the efficiency of clinical trials. The selection of COAs for randomized, clinical trials (RCTs) has been increasingly gaining the attention of many public and private institutions (i.e., companies, scientific organizations, and regulatory agencies [RAs] [e.g., FDA and European Medicines Agency (EMA)]). Health outcomes measurement in RCTs is an area of high interaction between several disciplines and different stakeholders. While stakeholders such as RAs advise on clinical endpoints to include in study protocols and provide approval for specific clinical endpoint measurements, others like private and public institutions create comprehensive libraries of instruments for COA measurements with description of their original psychometric properties obtained at validation stages. RAs are the main drivers for the final COAs and COA instrument selection, which guide the clinical endpoints required to claim a New Drug Application (NDA), followed by field experts on the therapeutic area. However, the definition of COAs provided by RAs is often not specific enough. Therefore, the disease-specific guidance issued is open to discussion, and consequently COA instrument selection requires a more interdisciplinary methodology.
Design: We review the strategies used by different stakeholders for COA selection. In this context, we defined stakeholders as A) pharma industry, B) independent researchers, C) expert consultants, D) vendors, and E) alliances among stakeholders. As for selection strategies, we defined the use of A) RA guidance, B) results from published meta-analysis, C) literature reviews, D) libraries of COAs, E) libraries of instruments, F) authors of the specific instruments, G) key opinion leaders for specific diseases, H) new COAs validation set for specific drug development plans, and I) initiatives to systematize the selection as decision tools (i.e., checklists for COAs selection and for COAs instrument selection). Examples of each one of the listed were provided, and strengths and weaknesses were analyzed for each one. We review the use of an efficacy-based selection approach within existing COA selection strategies.
Results: Different examples for each above specified strategies and stakeholders’ categories were identified based on specific searches on public databases and authors’ experience in the field. Examples of identified strategies are systematic reviews (e.g., Core Outcome Measures in Effectiveness Trials [COMET] initiative), checklists for patient-reported outcome (PRO) selection (e.g., Consensus-based Standards for the Selection of health Measurement Instruments [COSMIN]), Evaluating the Measurement of Patient-Reported Outcomes [EMPRO]), or even a PRO dimensional approach, such as the Patient Reported Outcomes Measurement Information System (PROMIS). Furthermore, other strategies exist coming from alliances, such as pharma, academia, patients, and public health bodies, promoting COA identification, selection, and validation, as is sometimes the case with Innovative Medicines Initiative (IMI), National Institute of Mental Health Research Domain Criteria (NIMH–RDoC), specific funding actions, such as foundations and university chairs, and task force groups within scientific societies, such as European College of Neuropsychopharmacology Targeted Network Meetings (ECNP-TNM) and The International Society for CNS Clinical Trials and Methodology (ISCTM).
Conclusion: The number of trial failures in the neurosciences makes COAs and COA instrument selection especially critical. A review of the state of the art regarding all initiatives to improve COA and COA selection process is presented. Overall innovative approaches on endpoint selection will require an approach focused on efficacy based COA selection requiring pre-competitive actions in order to 1) confirm the psychometric features of COAs completed in clinical trials (global and by country-language), 2) explore potential derived composite scores as clinical surrogates or endpoints, 3) confirm efficiency of COAs used in past trials at global and by country-language level, 4) explore feasibility of core outcome set (COS) specific for indications, based on qualitative and as well as quantitative methods. Initiatives do exist in the European Union and United States, but there is a need to describe the state of the art, to set a framework for all this activity, and to highlight the weaknesses and strengths of the existing ones, ideally those available to drug developers, and end users (i.e., clinical trial designers and scientists). Within the existing initiatives a more efficacy-based approach for COAs needs to be explored.