‘Improving health and wellbeing

through Research’

Preston Football Club17th October 2014

Improving health and wellbeing through research – October 2014

Dr Salman KarimConsultant Psychiatrist

“Dementia Clinical Trials”

Theme:Developing

Clinical Research

Improving health and wellbeing through research – October 2014

Clinical Trials in Alzheimer's Disease

Dr Salman KarimConsultant 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 ABT-

126 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

ChAT

NT

NT

Cholinergic Neuron

Target Neuron

Effector Neuron

NT

Choline +

Acetyl-CoA

ACh

AChACh

AC

h

α7

NT

Na+ NT

NT

NT

ChATCholine + Acetyl-CoA

ACh

NT

NT

α7 activation ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine

α7 activation ↑ neurotransmitter release e.g. ACh, glutamate, GABA, serotonin, and dopamine

α7

α7

Na+

Ca++

Ca++

ERK CREB

ACh

Activation of

presynaptic a7 nicotinic receptors potentiates synaptic transmission

Activation of

presynaptic a7 nicotinic receptors potentiates synaptic transmission

Ca++

Cholinergic Neuron

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.

Postsynaptic α7 Receptors

Presynaptic α7 Receptors

↑ intracellular Ca++ activates pro-cognitive signal transduction pathways

Na+

ACh

ACh

ACh

ACh

ACh

ACh

ACh

α7ERK CREB

Ca++

= ACh, Glu, GABA, 5-HT, DA

NT

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

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

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.

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 PalmerClinical Research Nurse Manager

“What our nurses can offer you”

Theme:Developing

Clinical Research

Improving health and wellbeing through research – October 2014

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 Team

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.

The Service

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

What is the NIHR Portfolio?

All NIHR Portfolio adopted studies can be found on the UK Clinical Research Network (UKCRN) Portfolio website:

http://public.ukcrn.org.uk/search/

Where to find portfolio studies

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

What to do if you want to know more about a study

Views of a participant and Carer

Please click:‘A participants experience of Dementia Research’

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

How to register an interest for assistance

Any questions?