‘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
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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
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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
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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
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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
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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
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
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?