Professional Documents
Culture Documents
Godwill Karikari, Zain Habashneh, Niyan Hamid, Oben Gul, Consolata Kerich,
Balasubramani Kapu Parasuraman, Klesta Durraj
• Alzheimer’s disease is the most common form
of dementia (more than half of all dementia
cases diagnosed)[1].
• This disease is a progressive, irreversible brain
disorder ( a neurodegenerative disease) and
affects memory and thinking skills of a
sufferer.
• The cause(s) of this disease is/are not
completely understood but 2 major possible
factors are plaques and tangles.
• Studies have shown that prevalence doubles
every 5 years after the age of 60[2] with 360,
000 new cases reported yearly.
Reference:
1. Scott T, O'Connor A, Link A, Beaulieu T. Economic analysis of opportunities to accelerate
Alzheimer's disease research and development. Annals of the New York Academy of
Sciences. 2014;1313(1):17-34.
2. Cummings J. Alzheimer Disease. JAMA. 2002;287(18):2335.
1) Amyloid
• Accumulation of insoluble brain Aβ protein [3]
2) Non-amyloid (tau accumulations)
• Excessive or abnormal phosphorylation of tau protein [4]
• NMDA glutamate receptor hypo-function hypothesis [3]
[5]
References:
3. Wright JW, Harding JW (2016). Small Molecule AngIV-based Analogs to Treat Alzheimer’s Disease. Int J Drug Dev & Res [Online] Available at:
http://www.ijddr.in/drug-development/small-molecule-angivbased-analogs-to-treat-alzheimers-disease.php?aid=9486 [Accessed 30 11 2018]
4. Zheng, H., Fridkin, M., & Youdim, M. (2014). From single target to multitarget/network therapeutics in Alzheimer's therapy[Online] Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942689/ [Accessed 30 11 2018]
5. Folch, J., Busquets, O., Ettcheto, M., Sánchez-López, E., Castro-Torres, R. D., Verdaguer, E., Garcia, M. L., Olloquequi, J., Casadesús, G., Beas-Zarate, C.,
Pelegri, C., Vilaplana, J., Auladell, C., … Camins, A. (2018). Memantine for the Treatment of Dementia: A Review on its Current and Future Applications [Online]
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870028/ [Accessed 30 11 2018]
Sample Size in Phase III
Step Summary
Objective Clinical Superiority
Error Type I error α = 0.05
Type II error β = 0.2, power 1 − β = 0.8
Effect size h=0.2
Estimated sample size 400 in each arm
Level of significance – It is typically taken as 0.05. The sample size increases as level of
significance decreases.
Power – It should be >= 0.8. Sample size increases as power increases. Higher the
power, lower the chance of missing a real effect.
Clinically meaningful difference - To detect a smaller difference, one needs a sample
of large size. References:
Sample size required to demonstrate equivalence is highest and to demonstrate 6. Sakpal, T. V., 2010. Sample Size
Estimation in Clinical Trial. [Online]
equality is lowest.[6] Available at:
https://www.ncbi.nlm.nih.gov/pmc/ar
ticles/PMC3148614/
[Accessed 28 11 2018].
Study Type : Interventional (Clinical Trial)
Estimated Enrolment: 1200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking (Blinding): Double blind (Participant, Care Provider,
Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Listed Location France, Germany, Greece, Italy, Sweden,
Countries United Kingdom
Accepts Healthy No
Volunteers
Duration: 18 months
Expected Study Start Date : 04 December 2018
Expected Primary Completion Date: 04 June
2020
Expected Study Completion Date: 04 June 2020 Schematic diagram of trial design
References:
7. Lawlor, P. B., 2017. A Phase III Trial of Nilvadipine to Treat Alzheimer's Disease (NILVAD). [Online]
Available at: https://clinicaltrials.gov/ct2/show/NCT02017340 [Accessed 28 11 2018].
8. Torg, M., 2014. York Psychology. [Online]
Available at: https://sites.google.com/a/york.org/psych/1-psychsci/1-2placebo
[Accessed 28 11 2018].
9. Karunanithi, M., 2010. RCT Design block diagram. [Online] Available at: https://www.researchgate.net/figure/RCT-Design-block-diagram-The-study-is-a-prospective-randomized-comparison-of-a_fig3_41172517
[Accessed 28 11 2018].
Randomization Technique: Stratified Randomization
• Stratified randomization is selected in order to guarantee balance in the treatment groups in accordance
with the severity of AD in patients.
• Sample example10:
If the random number is: 0-4: give Treatment A; 5-9: give Treatment B.
Mild AD
Random number list 4 1 6 5
Treatment allocated A A B B
This trial is going to be
Subject Identifier 3 8 9 11 multicentered and consist
Moderate AD 1200 patients. That’s why
allocating of the patients will
Random number list 0 7 4 1 be done by a computer
Treatment allocated A B A A program called «Random
Allocation Software» 11
Subject Identifier 1 2 6 12
to avoid human errors.
Severe AD
Random number list 9 6 3 1
Treatment allocated B B A A
Subject Identifier 4 5 7 10
10. Hackshaw, A. (2009). A concise guide to clinical trials. Oxford: Wiley-Blackwell BMJ Books. p:80
11. Saghaei, M. (2004). Random allocation software for parallel group randomized trials. BMC Med Res Methodol.
Patient Patient
Inclusion Exclusion
Criterias Criterias
• Must have the ages in the range of 55-85 • Any medical or neurological condition other than
• Must have a clinical diagnosis of Alzheimer's Disease (AD) Alzheimer's Disease (AD) that can cause dementia.
consistent with the following: • Participation in any other drug, biologic, device, or clinical
• (NINCDS-ADRDA) study or any treatment within 30 days (or 5 half lives,
whichever is longer) prior to Screening.
• (DSM IV TR) criteria
• Participation in any other clinical study involving
• Subject (or subject's permanent caregiver) provide signed experimental medications for AD within the 60 days (or 5
and dated informed consent (or assent) and authorization half lives, whichever is longer) prior to Screening.
to use protected health information (PHI) in accordance
with national and local subject privacy regulations. • Any contraindications to having a brain Magnetic
Resonance Imaging (MRI).
• Must have a Mini Mental State Examination (MMSE) score
of 14 to 26 inclusive.
12.Single ascending dose study of B1B037 in participants with Alzheimer’s disease. [online] Available at: http://clinicaltrials.gov
Primary outcomes Secondary outcomes
ADAS-cog
MMSE
• Memory
• Ability to name objects
• Orientation
• Verbal/written commands
• Language
CDR-SB
• Praxis
• problem solving
• Mood
• Community affairs
• Behavioural
• Personal care
changes
RUD-lite
ADCS-cog
• Accommodation
• Cancellation
• Any hospitalization
• Maze task
13. Vellas, B., Andrieu, S., Sampaio, C., Coley, N. and Wilcock, G. (2008). Endpoints for trials in Alzheimer's disease: a European task force consensus. The Lancet Neurology, 7(5), pp.436-450.
14. Gad S. Clinical trials handbook. Hoboken: John Wiley & Sons, Inc.; 2009.
DESIGN
RECORDING
ICH E6 GCP MONITORING
REPORTING
ICH E1 - The extent of population exposure to asses Clinical Safety on Long Term
Treatment) [16]
ICH E7 - Studies in Support of Special Populations: Geriatrics [16]
Ethics Committee assessments
Protection of human Informed consent
rights [16] Insurance and Indemnity