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Phase III Clinical Trial

----- In Alzheimer's Disease ---


--

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]

Gold standard drug: Memantine (Namenda®)


New drug: (Drug-X)

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

 Good Clinical Data Management Practices (GCDMP)


 Data Management  Comply with Code of Federal Regulation (CFR)
[17] [18]
 Validation, Audit trail, Access control
 Data collection - Case Reports Form (CRF)
 Database lock in Phase III CT
References:
16. ICH Official web site : ICH [Internet]. Ich.org. 2018 [cited 28 November 2018].
Available from: https://www.ich.org/home.html

 General Data Protection Regulation


17. Hackshaw A, Paul E. A Concise Guide to Clinical Trials. Somerset: Wiley; 2011.
 Data Protection 18. European Medicines Agency [Internet]. Ema.europa.eu. 2018 [cited 28 November
2018]. Available from: https://www.ema.europa.eu
[19] 2016/679/EU 19. General Data Protection Regulation: The Impact on Clinical Trials and Data Subjects -
Clinical Trials Arena [Internet]. Clinical Trials Arena. 2018 [cited 3 December 2018].
Available from: https://www.clinicaltrialsarena.com/news/data/general-data-
protection-regulation-the-impact-on-clinical-trials-and-data-subjects-5937623-2/
Alzheimer’s disease clinical trial had an excessively high failure rate over the past two decades with 99.6% drugs failing. Almost all
phase III clinical trial have failed to meet pre-specified endpoints and only four drugs are approved. [1]
Promising Drugs Failed In Phase III [2]
DRUGS FAILED IN PHASE
REASON FOR FAILURE IN PHASE III
III
MONOCLONAL ANTIBODIES
No significant clinical benefit and developed
Bapineuzumab
vasogenic edema
No change in CSF levels of tau protein and mild
Solanezumab
vasogenic edema
Failed to demonstrate significant clinical efficacy
Gantenerumab
endpoint
GAMA SECRETASE INHIBITOR
Worsening functional ability and more adverse and
Semagacestat
side effects
NEUROCHEMICAL ENHANCERS
Did not show improved performance on AD
Idalopiridine References:
beyond what seen by donepezil 19. Hendrix, S. and Ellison, N. (2017). ARE ALZHEIMER’S DRUG FAILURES DUE TO INACTIVE
COMPOUNDS OR ARE WE DOING SOMETHING WRONG?. Alzheimer's & Dementia, [online] 13(7),
Due to GI toxicity and also not meet specified end p.P617. Available at: https://aanddjournal.net/article/S1552-5260(17)30915-9/fulltext [Accessed 21
Encenicline
points Nov. 2018].
20. Mehta, D., Jackson, R., Paul, G., Shi, J. and Sabbagh, M. (2017). Why do trials for Alzheimer’s
OTHER disease drugs keep failing? A discontinued drug perspective for 2010-2015. Expert Opinion on
Investigational Drugs, [online] 26(6), pp.735-739. Available at:
Failed to detect change in primary or secondary https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5576861/ [Accessed 21 Nov. 2018].
Dimebon
outcomes
Reasons for Alzheimer Drugs Failing in Phase Methods to overcome challenges in Phase III: [3]
III [2]
ü Target a more homogenous population in future
studies
§ Targeting the wrong pathological substrates
§ Concerns with drug development ü Phase II studies often use pivotal study standards
for success, including co-primary endpoints
§ Problem with raters
§ Problems with methodologies ü Applying more rigor to overall
§ Treatment too late development process
§ Wrong population selection ü Adequate Phase II testing
§ Elementary issues ü Optimized phase III clinical trial design
ü Modelling and Simulation
References:
21. Grignolo, A. and Pretorious, S. (2018). Phase III Trail Failures Costly, but
Preventable. [online] Parexel.com. Available at: Many failed studies showed no evidence of a
https://www.parexel.com/files/5014/7274/5573/ACT_Article.pdf [Accessed 21 Nov.
2018]. treatment benefit, however several studies
illustrated known problems in AD research. Some
failed studies blame population heterogenicity. [21]
Break down of average cost centre for phase III Alzheimers
disease
 Only 90% of all IND make it past Phase III CT. The aim is to
ensure that all previous CT phases are conducted
thoroughly to reduce chance of failure as the costs most
Site retention
phase III CTs equal and may exceed the sum of all 13%
Administrative staff
previous CTs phases. Site recruitment 23%
4%
 Experts on AD research and development estimate the
cost of new medicines is $5.9 billion (95% confidence
interval $3.7 to 9.5 billion) and could be reduced by $2.0
billion.[22]
 The average monthly out-of-pocket cost for Phase III
clinical trials for new AD-modifying treatment is
Site monitoring
16%
about $5.46 million per molecule in development –
almost the sum of the previous phases combined. [22]

References: Clinical procedure


22. Scott T, O'Connor A, Link A, Beaulieu T. Economic analysis of opportunities to 23%
accelerate Alzheimer's disease research and development. Annals of the New York
RN/CRA
Academy of Sciences. 2014;1313(1):17-34. 9%
24. Driving Drug Innovation and Market Access: Part 1-Clinical Trial Cost Breakdown | Data management
Center Point Clinical Services [Internet]. Centerpointclinicalservices.com. 2018 [cited 20 Physician 1%
November 2018]. Available from: https://www.centerpointclinicalservices.com/blog- Patient retention Patient recruitment
posts/driving-drive-drug-innovation-and-market-access-part-1-clinical-trial-cost- 8% 0%
breakdown/ 3%
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