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2002 Meeting Highlights
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ASENT 4th Annual Meeting

Thursday, March 14 - Saturday, March 16, 2002
Capital Hilton Hotel Washington, DC .

FROM SYNTHESIS TO FIRST IN HUMANS: PHARMACOLOGY & CHEMISTRY Edward D. Hall, PhD, Senior Clinical Director Pfizer Global Research & Development Ann Arbor Laboratories Drug discovery in the current era is mechanism driven rather than empirical. The initiation of a drug discovery project begins with some level of understanding of the role of the particular target mechanism in the disease in question. Initial target validation studies have already verified that the target receptor or enzyme is probably involved in the disease, and if possible, there has been a demonstration in either cell-based or in vivo disease models that a prototype pharmacological compound known to interact with the putative drug target can ameliorate the disease mechanism. Once this has been achieved, high throughput screens (HTS) are developed and appropriate compound libraries are screened. The "hits" from the screen are then triaged by chemists to identify the best templates for chemical synthetic programs, and their activity at the target site is confirmed by secondary screening. Through an iterative process, compounds with high affinity and selectivity for the target mechanism, good pharmaceutical and pharmacokinetic properties and pharmacological activity are then entered into preclinical development (i.e. toxicology). If they are demonstrated to possess a practical therapeutic index (safety margin), they are then graduated into Phase I studies to assess safety and pharmacokinetics in human volunteers upon single and multiple dose administration. If no problems are encountered, the compound then moves into Phase II development to determine safety in patients suffering from the target disease. A second goal of Phase II testing is to determine whether the compound possesses the expected disease-modifying efficacy. In the case of novel or unprecedented mechanistic targets, the observation that compounds which selectively target the putative disease mechanism are indeed therapeutic in animal disease models and/or humans represents proof of concept. In other words, if the compound works and can be demonstrated to be operating by the intended mechanism, this constitutes reasonable proof that pharmacological modification of the target is associated with attenuation of the disease or its symptoms. At present, there is increasing emphasis on the identification and use of either biochemical markers of disease and drug mechanism or imaging technologies that can demonstrate that the disease mechanism is effectively being modified and/or the drug is working by its intended mechanism.

In order to illustrate this proof of concept process at both the laboratory and clinical level, the development of the concept of the role of oxygen radical-induced lipid peroxidation (LP) in the context of acute spinal cord and brain injury will be reviewed together with the discovery that administration of the glucocorticoid steroid methylprednisolone in doses that inhibit post-traumatic LP is able to protect the injured spinal cord and brain and promote functional recovery in animals and man via inhibition of LP. Additional proof of the concept that LP inhibition was the explanation for the neuroprotective effects of high dose methylprednisolone therapy was later provided by the observation that the 21-aminosteroid tirilazad, which completely lack glucocorticoid activity, is equally effective with high dose methylprednisolone in protecting the injured spinal cord (and brain). The importance of lipid peroxidative events in acute ischemic and hemorrhagic stroke and other neurodegenerative models has been illustrated by the finding that tirilazad as well as newer non-steroidal antioxidant compounds are also neuroprotective in those instances. The use of LP-related biomarkers in plasma or CSF to facilitate further proof of concept in acute CNS injury will also be discussed.


PROOF OF CONCEPT IN PHARMACEUTICAL RESEARCH
Scott A. Reines, MD, PhD, Merck Research Laboratories, West Point, PA 19486 USA

A critical element of drug development in neuroscience is bridging the preclinical - clinical gap that exists for novel therapeutic agents. Animal models in psychiatry, and to a lesser extent in neurology, lack adequate validation as predictors of useful treatments for human illnesses. Negative trials often go unpublished, creating an overly optimistic body of literature that over-emphasizes successful results. Recent experience in our Substance P antagonist program includes Proof-of-Concept studies in patients with various types of pain, headache, motion sickness, chemotherapy-induced emesis, schizophrenia, or depression. A study in a human model of motion sickness was also conducted. Although each of these potential indications was supported by preclinical efficacy models of uncertain predictive value, some (e.g. antagonism of cisplatin-induced emesis in ferret) had more obvious face validity than others. In another program we utilized a human model of anxiety to support further trials with a novel anxiolytic drug. Perspectives obtained from these programs will be discussed during the Panel Discussion.

PREFRONTAL NEURONS AND THE GENETICS OF SCHIZOPHRENIA
Daniel R. Weinberger, MD

Studies of prefrontal neurocognition and functional neuroimaging of prefrontal information processing consistently reveal abnormalities in patients with schizophrenia. Both the physiologic abnormalities and the cognitive deficits are predicted by a cellular measure in dorsolateral prefrontal cortex (DLPFC) – low N-acetyl aspartate (NAA) signals from MR spectroscopy. In pharmacologic imaging studies, patients manifest excessive dopamine release induced by amphetamine, an abnormality also predicted by low NAA in DLPFC. These findings suggest that abnormal function of the working memory cortical system (associated with positive symptoms) represent emergent properties of specific DLPFC neuronal pathology. Abnormalities of prefrontal information processing also are found in unaffected individuals who are genetically at risk for schizophrenia, suggesting that genetic polymorphisms affecting prefrontal function may be susceptibility alleles for schizophrenia. One such candidate is a functional polymorphism in the COMT gene that markedly affects enzyme activity and that appears to uniquely impact prefrontal dopamine. COMT genotype predicts performance on prefrontal executive cognition and working memory tasks. fMRI confirms that COMT genotype affects prefrontal physiology during working memory. Family based association studies have revealed excessive transmission to schizophrenic offspring of the allele (val) related to poorer prefrontal function. These various data provide convergent evidence that the COMT val allele increases risk for schizophrenia by virtue of its effect on dopamine-mediated prefrontal information processing – the first plausible biologic mechanism by which a specific allele affects variation in normal human cognition and risk for mental illness. These findings have implications for the development of novel treatments aimed at the prefrontal dopamine signaling cascade.


THE NEUROBIOLOGY OF MOOD DISORDERS
Dennis S. Charney, MD

There have been major advances in our understanding of the neurobiology of depression. The role of the monoamines, serotonin and norepinephrine have remained a focus. However, given the complexity of these systems, more refined hypotheses have been developed. In addition, it has become more clear that other neurotransmitter systems, neuropeptides, and intracellular molecular mechanisms may be equally or even more important in the etiology and treatment of depression. This presentation will update the audience on recent findings pertaining to these areas. Possible new approaches to the treatment of depression based upon this work will be presented.

DEVELOPMENT OF ATYPICAL NEUROLEPTICS
Richard C. Meibach, PhD

It has been 12 years since the first atypical neuroleptic was approved for use in the U.S. Since that time four additional drugs have entered the marketplace. Several more are in late stage of clinical development and should be submitted for approval in the near future. All of these compounds have in common qualities that differentiate them from first generation neuroleptics. They all share affinity for the dopamine (d2) receptor, but they bind with much lower affinity. They are all less selective in that they also bind with high affinity to serotonin receptors. All of these new compounds were developed in schizophrenic patients but due to their effects on improving positive symptoms were approved for the broader claim of treatment of the ‘manifestations of psychotic disorders’. New rating scales such as the SANS and PANSS were employed to further elucidate the effects on the negative symptoms and product labeling includes mention of these effects in the clinical trial section. Although it has been debated whether these new drugs offer greater efficacy it is well accepted that this class has significantly less extrapyramidal side effects than typical neuroleptics. Due to this greater safety margin, atypicals are being used in much broader patient populations today resulting in a 5 billion dollar market.

This presentation will highlight the clinical development of these compounds. Strengths and weaknesses of the individual study designs will be reviewed, as well as hurdles of using new rating scales in drug trials. Discussion will also include attempts to differentiate these drugs on the basis of both efficacy and safety. Clinical results in other areas including neurological uses will be presented. Finally, pre-clinical research is already exploring the next generation of antipsychotic medications. Some thoughts on how these may be developed in the clinic order to differentiate them from our current medications will be outlined.


ADVANCES IN NEUROPSYCHIATRY
K. Ranga R. Krishnan, MD

Two problems in trials of psychotropic medications are the use of placebo and the high placebo response. This leads to both ethical concerns and a number of failed trials. The ethical issue with regard to use of placebo has been well addressed for trials in depression and panic disorders where the risk with the placebo arm is small and there is a need for placebo to demonstrate that a drug has efficacy. Another issue is the potential use of surrogate markers in designing trials. In this presentation, I will discuss use of novel trial designs to minimize placebo exposure and the use of surrogates in Alzheimer’s disease. I will discuss play the winner as an example of a design that could be used to reduce the number of subjects exposed to placebo and also its potential as a design for proof of concept. The limitations and problems with this type of design will be discussed. The use of MRI imaging and MRS as a surrogate in AD trials will be discussed. Results from clinical trials will be presented to illustrate their use.

DESIGNING STROKE TRIALS
Barbara C. Tilley, PhD, Yuko Palesch, PhD
Medical University of South Carolina
Department of Biometry and Epidemiology

  1. Introduction
  2. Definitions
    1. Phase I
    2. Phase II
    3. Phase III
  3. Phase I Trials
    1. Common in studies of treatment for cancer.
    2. Examples of designs
      1. up-and-down method
      2. continual reassessment method
    3. Outcome measures
    4. Current NINDS-funded Phase I trial
  4. Phase II Trials
    1. Past Phase II Trials in stroke
    2. Phase II Trials in cancer research
    3. Design of Phase II Trials for stroke
    4. Types of error
    5. Choosing alpha and beta
    6. K-Stage
    7. Examples
      1. NINDS t-PA Trial
      2. TOAST
      3. Fospheyntoin
      4. Atlantis
      5. Current NINDS-funded Phase II trial
    8. Advantages
    9. Disadvantages
    10. Other comments
  5. Phase III Trials
    1. Choosing outcome measures
    2. Clinical Issues
    3. Using Global test statistics
      1. Why not Bonferroni
      2. Why not Hotelling’s T2
      3. Non-parametric procedure
      4. GEE
      5. Assumptions
      6. Properties
      7. NINDS example
      8. Uses outside of ischemic stroke trials
    4. d. Sample size
      1. Considerations
      2. (example using Barthel)
    5. Global
    6. Wilcoxon Rank Sum Test
    7. For comparing binary outcomes
    8. Composite outcomes
  6. Summary

References:

  • Atkinson EN, Brown BW, Herson J. KSTAGE—An interactive computer program for designing phase II clinical trials using predictive probability. Computers & Biomedicine 1982; 15:220-227. (lWebsite for program (http://odin.mdacc.tmc.edu/anonftp/)
  • Flemming T. One-sample multiple testing procedure for Phase II trials. Biometrics 1982; 38: 143-151.
  • Herson J. Phase II Trials in Buyse M. (ed) Cancer Clinical Trials Methods and Practice. Oxford University Press. NewYork, 1984; 223-257.
  • Herson J. Predictive probability early termination plans for phase II clinical trials. Biometrics 1979; 35:775-783.
  • Lefkopoulou M, Moore D, Ryan L. The analysis of multiple binary outcomes: An application to rodent teratology experiments. JASA 1989; 84:810-815.
  • O’Brien PC. Procedures for comparing samples with multiple endpoints. Biometrics 1984; 40:1079-1087.
  • O’Quigley J, Pepe M, Fisher L. continual reassessment method: a practical design for phase I clinical trials in cancer. Biometrics 1990; 46:33-48.
  • O’Quigley J. Estimating the probability of toxicity at the recommended dose following a phase I clinical trial in cancer. Biometrics 1992; 48:853-62.
  • Pocock SJ, Geller NL, Tsiatis AA. The analysis of multiple endpoints in clinical trials. Biometrics 1987; 43:487-498.
  • Storer BE. Design and analysis of phase I clinical trials. Biometrics 1989; 45:925-37.
  • Tilley BC, Marler J, Geller NL, Lu M, Legler JM, Brott T, et al. Use of a global test for multiple outcomes in stroke trials with application to the National Institute of Neurological Disorders and t-PA Stroke trial. Stroke 1996; 27:2136-2142.

CHOOSING ENDPOINTS IN NEUROLOGICAL TRIALS
Chris Weir, PhD

Several outcome measure frameworks represent the quality of life, impairment, disability and handicap dimensions of outcome. An ideal outcome measure will be valid, reliable and will be sensitive to important changes in health status. In the context of clinical trials it is also important that the outcome measure is relevant to the objective of the intervention under investigation. A further aspect often disregarded in clinical trials is that the outcome measure should address factors relevant to the individual patient. Taking clinical trials of putative neuroprotective or thrombolytic agents for acute ischemic stroke as a case study, I shall describe recent experiences in endpoint selection for several large influential clinical trials. Several types of endpoint have been utilized with varying degrees of success. Completed trials provide a resource of information regarding the appropriate dimensions of out come to measure, the statistical power of specific endpoints, and the size and pattern of treatment effects that may be observed. I shall outline how these experiences may also be used to guide the assessment of outcome in neurotherapeutic clinical trials in general. Finally, I shall describe in detail novel approaches that are currently under development for the selection of neurological trial endpoints. The performance of such methods will be compared to the properties of the ideal outcome measure and any potential gains in statistical power to identify efficacious therapeutics interventions will be assessed.


WHY NEUROLOGICAL THERAPEUTIC TRIALS WOULD FAIL
J Mau, G L Lenzi, and G J Del Zoppo
Department of Statistics in Medicine, Heinrich Heine University, Duesseldorf, Germany,
Department of Neurological Sciences, University "La Sapienza", Rome, Italy, and
Department of Molecular and Experimental Medicine, The Scripps Research Foundation, La Jolla, U.S.A.

Background & AIMS
Given the professional experience, the technical skills, the carefully planned protocols, and the peer expertise of advisers, one can hardly expect to see gross mistakes or a single cause for a negative stroke clinical trial. As the disease has many facets, so has each "drama" of a failed therapeutic investigation, and without sufficient knowledge about the pathobiology of ischemic stroke, neither will receive appropriate remedy. Past stroke clinical trials had tested quite a range of biochemical pathways, but even more impressive is the range of, or confusion about, metrics, designs and procedures to describe health deficits after an acute stroke and pertaining improvements quantitatively, to plan and to conduct the trials towards a "successful" trial outcome, respectively. Over-optimistic judgements and undue self-sufficiency in pharmaceutical companies, lack of quantitative knowledge about patient pools in hospitals, poor understanding of nosometrics, in particular in multidimensional disease outcomes, and little insight into specific needs for a trial setting at the design phase could represent some valid objections in recent and current clinical research. In a more systematic way, however, one would consider:

Dimensions and time frame of stroke recovery: What are the dimensions and time windows which one should target with a clinical efficacy trial?

Scales of efficacy outcome and "natural" course: What is known about scales in natural course of disease and where may one expect to see improvement?

Stroke clinical trials and societal context: Would differences of health care delivery affect multi-national trials and may one construe a legitimate claim for public access to data from industry-sponsored clinical trials?

Choice of endpoints: Combinations or multiplicity? Should multiple endpoints be combined to measure outcome in one dimension, and which endpoints does one declare as secondary?

Exploration of non-standard designs: Is there a point in multi-dose phase-III and in combination therapy trials? Are one-sided tests for efficacy ethical and scientifically sound?

Intercurrent mortality: Is it an endpoint or a confounder, are there other confounders, and does one have data on any of those others?

Methods
The core opinions of speakers at the International Workshop on STROKE NOSOMETRICS & DESIGN OF STROKE CLINICAL TRIALS, held in Duesseldorf, October 16-17, 1995, will be reported in a summary way. Some 30 clinicians, basic scientists and biostatisticians from Europe, North America and Japan, from academia, industry or governmental authorities, had discussed the clinical and methodological issues in the assessment of course of disease and, in particular, of outcome from therapeutical interventions after acute stroke.

Results

  1. Large parts of the brain remain disregarded by most scales, and individualized time "windows" from onset of symptoms to treatment may be a needed option.
  2. Short-term assessments may be desirable, and items within scales may be weighted more objectively, but longer and closer coverage during follow-up would also have merits.
  3. The impact of health care delivery systems must be understood and addressed, and public access to data from industry-sponsored clinical trials should become a legitimate issue.
  4. The multiplicity of relevant endpoints must be understood in their chronology of expression and their pathobiological correlations and weighed against the insight provided by "global" approaches; the variability of profiles of outcome scales should be studied and addressed more adequately.
  5. The "dogmatic" use of the two-sided tests of significance may be questioned more often at the design stage, and intercurrent mortality, in particular when related to treatment, should be incoporated into efficacy assessments.
  6. Combination therapy trials may become predominant in clinical research on acute stroke therapies, and the appropriate designs should be carefully selected according to clinical relevance; recently developed "adaptive" multi-stage designs will also need closer study.

Discussion
The workshop did not address the value of risk-benefit balances and the need for risk-profile analyses for individualized treatment decison for future patients. And it did not close with a checklist of avoidable errors, either. Instead, it had demonstrated the need for an awareness, to be taken more seriously and more openly into the many committees and boards by the experts and advisors, that day-to-day decisions are largely based on consensus than confirmed scientific evidence.

Conclusion
Encouraging tests in animal models and promising episodes of tolerable and effective treatment in few patients do not turn a subsequent negative phase-III trial into a deplorable failure for progress in therapeutical clinical research: it may well be a case of elimination of the obsolete. For an active agent, however, the race towards an NDA submission is endangered by substantial gaps of knowledge with respect to major constituents of a successful clinical test: understanding the pathobiology, and then applying insightful metrics, choosing endpoints which cover all relevant outcomes, and adopting a powerful design.


DECISION ANALYSIS IN NEUROLOGICAL DRUG DEVELOPMENT
Michael Krams, MD
Pfizer Global Research and Development, Sandwich, U.K.

Background
Developing new drug therapies for CNS indications can be an expensive high-risk operation. Much of the cost of bringing a new compound to market (>US$700M per successful candidate) is accrued during late phase II/III development. Traditionally, phase II/III trials do not formally look at a utility which accounts for cost of development and eventual pay-off, but concentrate on showing a clinically meaningful effect, using a desired effect size and estimated variability of the primary endpoint in isolation as the basis for sample size calculations. However, cost-benefit considerations are intrinsically governing the decision-making on go/no-go decision points for advancing drug development programs. Decision-making happens in discrete steps, at predefined time-points at which sufficient information is gathered. Improving the quality and speed of decision-making may translate into higher cost-efficiency in developing new drug therapies.

The failure to understand the dose-response of a new drug is one important reason for late attrition in drug development. We propose a decision-analytic approach to developing new CNS therapies and will use the example of developing a neuroprotectant for acute stroke to illustrate an adaptive design learning in real time about the dose-response and envisaging a seamless switch from a phase IIb dose-response finding phase to a confirmatory phase III trial. Rather than discussing specifics of choice of endpoint, compound related aspects and more complex issues on setting the overall utility, we will concentrate on the general concept of a highly innovative approach, parts of which have now been deployed in a real drug development program. The design presented here is discussed in more detail by Berry et al, 2002 (1).

Methods and Results
Let us envisage a neuroprotective treatment as a one-off iv-bolus, to be administered as soon as possible after the onset of an acute stroke. Primary endpoint is a continuous clinical outcome measure (say change from baseline to day 90 as measured by a neurological stroke scale). Let us assume that earlier measurements of the outcome parameter are predictive for final outcome. Relevant information about the patient is entered at baseline and at several follow-up time-points in real time, using a fax, web or palmtop based interface to a central computer system. Thus an information base accruing relevant patient outcome data is being built up. In a sequential adaptive dose-response finding study two decision problems are formally and continuously assessed, using a Bayesian decision-analysis.

  1. Which dose should the next patient be allocated to, in order to optimize learning about the minimal dose which will yield maximal efficacy (say ED95)?
  2. Should the dose-response finding phase continue in order to learn more about the dose-response (and the ED95 in particular), or is there sufficient information to now recommend stopping the trial, either for futility or to move into a confirmatory clinical trial, comparing the ED95 against control? Using Bayesian statistics the probability of achieving a predefined overall utility in a future confirmatory trial can be calculated. The overall utility may integrate desired clinical effect, cost of running the development program and estimated pay-off.

We used the Copenhagen Stroke Study (2) and a simulation software programmed by P Mueller (1) to run >100.000 simulated stroke trials and will present results comparing the simulated performance of a traditional dose-ranging study with the decision-analytic approach.

Discussion and Conclusion

A decision-analytic approach and simulation-guided clinical trial design have the potential to

  1. enhance the quality and
  2. speed up the process of decision-making, leading to remarkable advantages for the overall cost-efficiency in the development of neurological drug therapies.

The underlying philosophy of applying decision-analysis to clinical drug development is of interest well beyond the indication of acute stroke. In our presentation we will lay out the potential for future applications.

References

  1. Berry DA, Mueller P, Grieve AP, Smith MK, Parke T, Krams M (2002) Bayesian Designs for Dose-Ranging Drug Trials. In: Case Studies in Bayesian Statistics Vol 5, ed. by Gatsonis C, Kass RE, CarlinB, Carriquiry A, Gelman A, Verdinelli I, West M, Springer-Verlag, New York.
  2. Jorgensen HS, Nakayama H, Raaschou HO, Vive-Larsen J, Stoier M, Olsen TS (1995) Outcome and time course of recovery in stroke. The Copenhagen Stroke Study..Arch Phys Med Rehabil 76:399-4122

 

FROM SYNTHESIS TO FIRST IN HUMANS: PHARMACOLOGY & CHEMISTRY
Edward D. Hall, PhD, Senior Clinical Director
Pfizer Global Research & Development
Ann Arbor Laboratories

Drug discovery in the current era is mechanism driven rather than empirical. The initiation of a drug discovery project begins with some level of understanding of the role of the particular target mechanism in the disease in question. Initial target validation studies have already verified that the target receptor or enzyme is probably involved in the disease, and if possible, there has been a demonstration in either cell-based or in vivo disease models that a prototype pharmacological compound known to interact with the putative drug target can ameliorate the disease mechanism. Once this has been achieved, high throughput screens (HTS) are developed and appropriate compound libraries are screened. The "hits" from the screen are then triaged by chemists to identify the best templates for chemical synthetic programs, and their activity at the target site is confirmed by secondary screening. Through an iterative process, compounds with high affinity and selectivity for the target mechanism, good pharmaceutical and pharmacokinetic properties and pharmacological activity are then entered into preclinical development (i.e. toxicology). If they are demonstrated to possess a practical therapeutic index (safety margin), they are then graduated into Phase I studies to assess safety and pharmacokinetics in human volunteers upon single and multiple dose administration. If no problems are encountered, the compound then moves into Phase II development to determine safety in patients suffering from the target disease. A second goal of Phase II testing is to determine whether the compound possesses the expected disease-modifying efficacy. In the case of novel or unprecedented mechanistic targets, the observation that compounds which selectively target the putative disease mechanism are indeed therapeutic in animal disease models and/or humans represents proof of concept. In other words, if the compound works and can be demonstrated to be operating by the intended mechanism, this constitutes reasonable proof that pharmacological modification of the target is associated with attenuation of the disease or its symptoms. At present, there is increasing emphasis on the identification and use of either biochemical markers of disease and drug mechanism or imaging technologies that can demonstrate that the disease mechanism is effectively being modified and/or the drug is working by its intended mechanism.

In order to illustrate this proof of concept process at both the laboratory and clinical level, the development of the concept of the role of oxygen radical-induced lipid peroxidation (LP) in the context of acute spinal cord and brain injury will be reviewed together with the discovery that administration of the glucocorticoid steroid methylprednisolone in doses that inhibit post-traumatic LP is able to protect the injured spinal cord and brain and promote functional recovery in animals and man via inhibition of LP. Additional proof of the concept that LP inhibition was the explanation for the neuroprotective effects of high dose methylprednisolone therapy was later provided by the observation that the 21-aminosteroid tirilazad, which completely lack glucocorticoid activity, is equally effective with high dose methylprednisolone in protecting the injured spinal cord (and brain). The importance of lipid peroxidative events in acute ischemic and hemorrhagic stroke and other neurodegenerative models has been illustrated by the finding that tirilazad as well as newer non-steroidal antioxidant compounds are also neuroprotective in those instances. The use of LP-related biomarkers in plasma or CSF to facilitate further proof of concept in acute CNS injury will also be discussed.

ATTITUDES TOWARDS EMERGENCY RESEARCH CONSENT WAIVER AT A LEVEL 1 TRAUMA EMERGENCY CENTER
C. Contant 1, L. Mangus 2, C. Robertson 1, A. Valadka 1, B. Brody 2, 1Department of Neurosurgery and the 2Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, Texas 77030 USA

The NIH has provided procedures for conduct of research under an Emergency Research Consent Waiver (ERCW). Under this rule, consultation with the "at risk" community is required. A questionnaire was given to a gender and ethnicity stratified sample of 480 individuals in the Waiting Room of the Emergency Center of the Level 1 Trauma Center at Ben Taub General Hospital in Houston, Texas. A description of an on-going study in patients with sever brain trauma being conducted at Ben Taub was given. Participants were then asked five primary questions, followed by several demographic questions. The primary items assessed attitudes towards the relative risks/benefits of the study, the use of randomization and ERCW, conduct of the study in a public hospital and whether the respondent would wish to be enrolled in the study, if needed. Each item was asked in a "positive" or "negative" manner. Log-linear models were fit to examine the effects of gender, ethnicity and the manner of asking the question for the primary items. Relatively few interactions among these factors were found. A high proportion of the respondents (86.6%) were willing to enroll themselves or a family member in the study if needed. Use of randomization and waiver received less positive approval (53% and 59% respectively). The overall high personal acceptance of the clinical study was tempered by some concern over the policy of randomization and waiver. Emergency room waiting area surveys may provide an in-depth understanding of the attitudes of the population at risk for ERCW.

Supported by NINDS.


EXPERIENCE WITH NEW ENTERIC-COATED WEEKLY FLUOXETINE
S. Levy, Philadelphia College of Osteopathic Medicine, Westchester, PA 19380; J.M. Plewes, M.G. Wilson, Eli Lilly and Company, Indianapolis, IN 46285

A new formulation enteric-coated fluoxetine given once weekly has been shown in clinical trials to be well tolerated, effective and associated with greater compliance. However, there have been few literature reports on its use in naturalistic clinical sitting. Seventy-one psychiatric outpatients with a confirmed diagnosis of clinical depression from our clinic participated. They were stable, in complete remission and had been compliant on their daily fluoxetine for an average of 3.1 years. Four patients began weekly dosing as a part of their acute therapy. We extracted data from patient charts, and we collected a quantitative evaluation of the severity of their depression. All patients were successfully converted from a single daily dose to a single weekly dose. All patients including the four acute therapy patients are presently in remission. This cohort has been monitored and has a cumulative exposure of 32.1 patient-years. A statistically significant average improvement of 21.0 points, with a standard error of 1.8, from beginning of acute therapy to follow-up on weekly dosing on the modified Zung was observed (p-value < 0.001). No serious adverse events or hospitalizations were reported for any patient. In our community-based outpatient psychiatric clinic, we see patients with substantial medical and psychiatric comorbid disorders. In a subgroup of this population, we observed that weekly doses of enteric-coated fluoxetine were tolerable and effective for long-term continuation treatment of major depressive disorder. The simple, once weekly, higher dosing offers a convenient alternative for some patients during long-term treatment of depression.

Funding provided by Eli Lilly and Company


ALZHEIMERS DISEASE (AD) PATIENTS’ AND CAREGIVERS’ CAPACITY, COMPETENCY, AND REASONS TO ENROLL IN AN EARLY PHASE AD CLINICAL TRIAL.
J.H.T Karlawish, D.J. Casarett, B.D. James, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

To examine AD patients’ and caregivers’ (CG’s) capacity, competency and reasons for enrolling in an early phase AD clinical trial, interviews were conducted with 15 mild-moderate AD patients, 15 age and education matched nondemented elderly persons, and 15 CG’s. Capacity was measured using the MacArthur Competency Assessment Tool for Clinical Research, competency was judged by a study coordinator who reviewed tape recordings of the capacity interviews, and the reasons for a decision were determined by coding of the capacity interviews. On all measures except the ability to make a choice, patients performed worse than controls (understanding p=0.001; appreciation p=0.005; reasoning p=0.0005), and CG’s (understanding p=0.0002; appreciation p=0.003; reasoning p=0.0003). Using the controls’ performance to set psychometric criteria to define capacity, the proportions of patients with adequate understanding, appreciation and reasoning were: 6/15 (40%), 3/15 (20%) and 5/15 (33%). All CG’s and 8/15 (53%) patients were competent. Reasons for enrolling typically featured the potential benefit to the patients’ health or well-being, and altruism expressed either as a desire to help other patients or family, or a desire to contribute to scientific knowledge. The MacCAT-CR is a reliable and valid way to assess patient capacity and competency to enroll in an early phase clinical trial. While many patients have significant impairments in their capacity, some mild stage patients are competent. Reasons to enroll in an early phase trial blend an expectation of therapeutic benefit and a desire to help others.


NEOTROFINTM IS NEUROPROTECTIVE IN AN ANIMAL MODEL OF PARKINSON’S DISEASE
F.J. Huff, N. Hauptmann, M.Yan, and D.R. Helton, Discovery Research, NeoTherapeutics, Irvine, CA, USA

NeotrofinTM (AIT-082) has been shown to improve memory in both animals and humans. In animal models, Neotrofin has been demonstrated to have neuroprotective and neuroregenerative properties. Currently, Neotrofin is in late stage clinical trials for the treatment of Alzheimer’s disease. The purpose of this study was to determine if Neotrofin would exhibit neuroprotective activity in a model of Parkinson’s disease in the rat. Circling behavior and altered dopamine metabolism were evaluated in unilaterally 6-OHDA-lesioned rats. Rats were administered Neotrofin or vehicle 15 minutes before lesioning of the substantia nigra and Day 1 and daily thereafter for 30 days. Apomorphine administration and behavioral monitoring was performed every third day beginning on Day 15. Neotrofin (10 mg/kg, s.c.) reduced the rotations induced by apomorphine relative to controls. In addition to the decrease in response magnitude, the onset of the rotations produced by apomorphine was delayed in rats treated with Neotrofin. These results indicate that Neotrofin partially protects nigrostriatal dopaminergic neurons from the neurodegeneration produced by the toxin 6-OHDA. These results extend previous data showing that Neotrofin is neuroprotective and support its use as a potential therapy of Parkinson’s disease. A phase IIA clinical study of Neotrofin in patients with early stage Parkinson’s disease is currently ongoing.


THE DEVELOPMENT OF A NOVEL SERIES OF COMPOUNDS FOR THE TREATMENT OF PSYCHOSIS AND MOOD-RELATED DISORDER
D. Helton, E. Pfadenhauer, P. Mohan, and E. Taylor. Discovery Research, NeoTherapeutics, Irvine, CA, USA

We have synthesized a series of antipsychotic compounds. These novel compounds have been designed to have cognitive enhancing properties and a restricted receptor profile, thus targeting the basic symptoms of schizophrenia and intractable symptoms of schizophrenia (i.e. cognitive impairment), while minimizing secondary pharmacology commonly associated with antipsychotics. We characterized the behavioral, neurochemical, biochemical, and toxicological activity of select compounds. As examples of the series, NEO-356 and NEO-377 have selective dopaminergic and serotinergic receptor binding activity and little to no adrenergic, histaminergic or muscarinic receptor binding. Both compounds reverse PCP-induced disruption of pre-pulse inhibition indicating that they may have clinical utility in the treatment of psychosis. NEO-377 also disrupts conditioned avoidance responding (CAR) indicating that like other atypical antipsychotics, it may disrupt cognition. However, NEO-356 does not disrupt CAR and may therefore represent a structural class that enhances cognition. NEO-356 attenuates PCP-and not MK-801-induced hyper-locomotion, whereas NEO-377 attenuates MK-801-and not PCP-induced hyper-locomotion. These two examples highlight the functional diversity of the series. The characterization of several compounds in comparison to clozapine and risperidone will be represented.


DELUSIONS IN AD ARE LINKED TO DEMENTIA SEVERITY, ESPECIALLY FRONTAL-LOBE IMPAIRMENTS
C. Walulik, J. Locascio, M. Korczykowski, and J.H. Growdon, Massachusetts General Hospital, Boston, MA 02114

The purpose of this study was to determine if behavioral disturbances in probable AD patients correlate with either global estimates of dementia severity or specific cognitive impairments. 64 probable AD patients completed a set of 4 examinations within 3 months: the information-memory-concentration subscale of the Blessed Dementia Scale (BDS) and a set of formal cognitive tests were administered to each patient, and the Activities of Daily Living questionnaire (ADL) and the Neuropsychiatric Inventory (NPI) were completed by the caregiver. The data were analyzed by Pearson correlation coefficients. Analyses from the NPI were limited to these domains: depression, delusions, and hallucinations. Of these three, only delusional frequency (p<0.002) and severity (p<0.0007) correlated with extent of dementia severity. Within the set of cognitive tests, delusions correlated with deficits on frontal-lobe tests such as the Stroop test (p<0.02) and verbal fluency for letters (p<0.03). Overall, these findings reinforce the association between delusions and frontal lobe dysfunction in AD.

This project was funded by the Alzheimer’s Disease Research Center at the Massachusetts General Hospital (P50 AG05134).

 

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