‘Improving health and wellbeing through Research’ Preston Football Club 17 th October 2014

1. ‘Improving health and wellbeing through • Research’ • Preston Football Club • 17th October 2014 Improving health and wellbeing through research – October 2014

2. Dr Salman Karim • Consultant Psychiatrist • “Dementia Clinical Trials” Theme: Developing Clinical Research Improving health and wellbeing through research – October 2014

3. Clinical Trials in Alzheimer's DiseaseDr Salman Karim Consultant Psychiatrist/Honorary Senior Lecturer Lancashire Care NHS Foundation Trust University of Manchester

5. 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

6. 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

7. 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

8. 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

10. 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

13. 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

14. MANAGEMENT • Medications Cholinesterase inhibitors (Donepezil, Rivastigmine, Galantamine) Memantine • Non pharmacological interventions

17. 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

18. 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

19. 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

20. Local Challenges • Staff Training • Bureaucracy • Developing partnerships • Risks/benefits

21. 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 ABT-126 in mild-to-moderate AD. • RCT to evaluate safety and sfficacyof ABT-126 in Cognitive Deficits in Schizophrenia.

22. Neuronal Nicotinic Receptors

23. Na+ Postsynaptic α7 Receptors ↑ intracellular Ca++ activates pro-cognitive signal transduction pathways Ca++ ACh α7 Ca++ Cholinergic Neuron α7 Choline + Acetyl-CoA ACh ACh ChAT ACh ACh ACh ACh ACh ACh ERK  CREB α7 Presynaptic α7 Receptors = ACh, Glu, GABA, 5-HT, DA Choline + Acetyl-CoA Cholinergic Neuron Effector Neuron NT ChAT Activation of presynaptic a7nicotinic receptors potentiates synaptic transmission α7 activation  ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine NT NT NT NT Na+ Ca++ ACh α7 NT ACh Na+ Ca++ NT ACh Reviewed in: Stahl SM. J Clin Psychiatry. 2000;61(9):628-9. Bitner RS, Nikkel AL, et al., Brain Research. 2009;1265:65-74. NT ACh ACh Target Neuron ERK  CREB NT NT α7 Receptors: Pre- and Postsynaptic Mechanisms

24. Clinical Trials in LCFT • Increased cortisol in AD • ABT-384 is a selective 11-β-hydroxysteroid 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

25. Clinical Trials in LCFT • Novel Histamine H3 receptor antagonist S38093 • Efficacy and safety of S38093 Vs placebo in co-administration with donepezil in patients with moderate AD. A 24 week international, multi-centre, randomised, double-blind, placebo-controlled phase IIb study S38093

26. Clinical Trials in LCFT 5HT6 receptor antagonist (Lu AE58054) blocking GABA-ergic excitation • RCT of Lu AE58054 in patients with mild-moderate Alzheimer’s disease treated with an acety-cholinesterase inhibitor.

27. 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.

28. Vision for Future • To develop a clinical research facility • To expand clinical trials portfolio • To build a team of researchers

29. Thank you!

30. Karen Palmer • Clinical Research Nurse Manager • “What our nurses can offer you” Theme: Developing Clinical Research Improving health and wellbeing through research – October 2014

31. 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.

32. 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.

33. 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

34. 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/

35. What to do if you want to know more about a study • Contact the Research department at Research@lancashirecare.nhs.uk 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

36. Views of a participant and Carer Please click: ‘A participants experience of Dementia Research’

37. How to register an interest for assistance

38. Any questions?