‘Improving health and wellbeing through Research’ Preston Football Club 17th October 2014 Improving health and wellbeing through research – October 2014 Dr Salman Karim Consultant Psychiatrist “Dementia Clinical Trials” Improving health and wellbeing through research – October 2014 Theme: Developing Clinical Research Clinical Trials in Alzheimer's Disease Dr Salman Karim Consultant Psychiatrist/Honorary Senior Lecturer Lancashire Care NHS Foundation Trust University of Manchester EPIDEMIOLOGY • • • • • 700,000 people in UK 17-25 million people worldwide Expected to rise to 30-40 million Incidence reported higher in the west (2%) Prevalence doubles every 5 years below 5% in 30-65 years above 10% in over 80 years EPIDEMIOLOGY • • • • • • Cost of care in UK is 4 billion per year In North America its 100 billion dollars 25% hospital cost 75% residential care cost Does not include carers burden Phenomenal rise expected in future RISK FACTORS • Age Risk doubles every 5 years after 60 • Genetic predisposition (ApoE E4) Inability to remove amyloid plaque Tau accumulation Loss of neurons • Vascular risk factors • Head trauma NEUROPATHOLOGY • Senile Plaques : Extra-cellular amyloid beta-peptide • Neurofibrillary Tangles : Intra-cellular fibrillary proteins • Reduction of neurons and synapses • Reduction in cellular energy metabolism • Neuronal dysfunction/ death Neurotoxic action of Beta amyloid • • • • • • Oxidative stress Impaired cellular metabolism Mitrochondial dysfunction Impaired calcium metabolism Impairment of long term potentiation Increased neuro-fibrillary tangle formation Neurochemistry of Alzheimer’s disease Acetylcholine: • Perception, Attention, Learning, attention, Cognition and judgement Noradrenaline: • Alertness, Memory and Attention Serotonin: • Regulation of appetite and emotions Glutamate (excitatory neurotransmitter ): • Neuronal cell death in many conditions is mediated by the effects of glutamate MANAGEMENT • Medications Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) Memantine • Non pharmacological interventions Developing New Drugs for Alzheimer's Disease Identifying target areas: • Beta amyloid clearance • Tau protein clearance • Enhancing neurotransmission Developing biological makers of AD: • Blood markers • CSF markers • Imaging Challenges Cost of developing new drugs • Average cost 1.2 billion including failures • 101 clinical trials on AD since 1998 • 3 drugs licenced Time scale • Drug discovery/preclinical: 3-6 years • Clinical trials (phase I, II and III): 6-7 years • Licensing: 0.5-2 years Local Challenges Increasing complexity of protocols • Physical investigations (bloods, ECG, Imaging, CSF) • Pharmacy • Facilities Developing the team with skill mix • Medical staff • Nursing staff • Skilled raters Local Challenges • • • • Staff Training Bureaucracy Developing partnerships Risks/benefits Clinical Trials in LCFT Nicotinic receptor targeted trials: • RCT to evaluate the efficacy and safety of ABT-126 in mild to moderate AD. • Long-term safety and tolerability of ABT126 in mild-to-moderate AD. • RCT to evaluate safety and sfficacy of ABT-126 in Cognitive Deficits in Schizophrenia. Neuronal Nicotinic Receptors α7 Receptors: Pre- and Postsynaptic Mechanisms Na+ Postsynaptic α7 Receptors Cholinergic Neuron Ca++ Choline + AcetylCoA ChAT ACh ↑ intracellular Ca++ activates proCa++ cognitive signal α7 ERK CREB transduction pathways α7 ACh Presynaptic α7 Receptors = ACh, Glu, GABA, 5-HT, DA Cholinergic Neuron Activation of presynaptic a7 nicotinic receptors potentiates synaptic transmission Target Neuron ACh NT NT NT ERK CREB Effector Neuron α7 activation ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine Reviewed in: Stahl SM. J Clin Psychiatry. 2000;61(9):628-9. Bitner RS, Nikkel AL, et al., Brain Research. 2009;1265:65-74. Clinical Trials in LCFT • Increased cortisol in AD • ABT-384 is a selective 11-βhydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor • RCT to evaluate the efficacy and safety of ABT-384 in subjects with Mild-to Moderate Alzheimer’s Disease Clinical Trials in LCFT • Novel Histamine H3 receptor antagonist S38093 • Efficacy and safety of S38093 Vs placebo S38093 in co-administration with donepezil in patients with moderate AD. A 24 week international, multi-centre, randomised, double-blind, placebo-controlled phase IIb study Clinical Trials in LCFT 5HT6 receptor antagonist (Lu AE58054) blocking GABA-ergic excitation • RCT of Lu AE58054 in patients with mildmoderate Alzheimer’s disease treated with an acety-cholinesterase inhibitor. Clinical Trials in LCFT • Mono-clonal antibodies (beta amyloid removal) • RCT of efficiency and safety of Gantenerumab in subjects with mild AD. • RCT of efficiency and safety of Gantenerumab in subjects with mild AD: PET scan sub study. Vision for Future • To develop a clinical research facility • To expand clinical trials portfolio • To build a team of researchers Thank you! Karen Palmer Clinical Research Nurse Manager “What our nurses can offer you” Improving health and wellbeing through research – October 2014 Theme: Developing Clinical Research The Team Karen Palmer – Clinical Research Nurse Manager Kelly Wigglesworth – Research Nurse Daniel Pulford – Clinical Studies Officer Andrea Houlding – Research Secretary Sit within the Corporate Network under the Research department and are a generic trust research resource. The Service We provide support to clinical services who are approved to conduct a NIHR portfolio adopted research study. Support is tailor made to researchers needs. Including educational support for researchers and clinical staff. Along with the conduct of all clinical and administrative aspects of the research process. What is the NIHR Portfolio? The NIHR (National Institute for Health Research) requires Trusts to conduct high quality research. This is research which is grant funded through competitive means and has been adopted onto a portfolio of registered national projects. These projects are monitored against their achievement of the recruitment target and the delivery of the research findings Where to find portfolio studies All NIHR Portfolio adopted studies can be found on the UK Clinical Research Network (UKCRN) Portfolio website: http://public.ukcrn.org.uk/search/ What to do if you want to know more about a study Contact the Research department at [email protected] and quote the following information: Project reference number (as shown on the website) Project title The team will then make contact with the researcher on your behalf and request further information. This information can be assessed jointly and a decision can be made on the services ability to support the study and staff capacity Views of a participant and Carer Please click: ‘A participants experience of Dementia Research’ How to register an interest for assistance A portfolio research study is identified to sit within you clinical team A review of resources will take place between you and the research dept to facilitate the research If a need is identified the research dept will refer you to the research nurses Any questions?