Case Study: Dementia

ClinActis Pte Ltd - 112 Robinson Road - #06-04 - Singapore 068902 Telephone: +65 6436 5500 - [email protected]

Case Study: Dementia CNS

ClinActis is exclusively focused on Asia Pacific, with solid expertise in applying international quality standards to regional specificities. ClinActis is flexible in our approach to work scope and budgeting and contracting process. Delivering Quality to Our Clients ClinActis is committed to implementing international standards in clinical trials. Our ability to deliver high quality results to our clients is based on recruiting and maintaining the best talent within our organization. ClinActis’ senior management is fully accountable for the quality of deliverables to our clients.


Your Proactive Clinical Research Partner in Asia Pacific

ClinActis Pte Ltd is a full service CRO providing clinical trial services to the pharmaceutical, medical device, medical nutrition and biotech companies in Asia Pacific. Established in 2009, ClinActis Pte Ltd is headquartered in Singapore. ClinActis Value Proposition ClinActis is a multicultural company. As such, the team is able to communicate effectively with international clients.


Mission and Vision With headquarters based in Asia, all corporate

decisions are made within the region, in order to better anticipate our client needs and adapt to local specificities. Vision Our vision is to become the reference CRO specialized in conducting clinical research in Asia Pacific, offering state of the art quality services, with cost effective solutions. We strive to employ people with genuine expertise in the region and with a passion for excellence, to work with our clients in the most pro-active way, and to build a relationship based on trust, transparency and strong ethics. Mission

Our mission is to provide our clients with unique and dynamic expertise in applying global drug development standards to the specificities of each country in the Asia Pacific region.

Christophe Tournerie, MD – Owner and CEO Dr. Tournerie has more than 20 years experience in clinical research in Europe and Asia Pacific including Japan, working with biotechnology companies, pharmaceutical companies and clinical research organizations. After completion of his medical studies in Paris and various hospital assignments in France, Dr. Tournerie spent a period of 3 years at the National Medical Research Institute in France in the field of drug development in anti-HIV products.


About Our Founder

His introduction to the pharmaceutical industry was as Medical Director in an American biotechnology company developing anti-HIV products. Then, he moved to a large global CRO, heading the Project management Department for South Europe, and then as Head of Operations in the Japan affiliate. Later, Dr. Tournerie headed the Asian clinical research activity for a multi-national Pharmaceutical Company, based in Singapore. More recently, Dr. Tournerie was Vice President Asia Pacific for a large global CRO, based in Singapore. During this assignment, Dr. Tournerie developed the business strategy for the region, successfully established and directed operations in 12 countries and built a highly professional team.


Operational Expertise – Regional Footprint

ClinActis Experience §  33 years experience in clinical

research in pharmaceutical and biotechnology companies as well as CROs

§  27 years experience in Asia Pacific, including Australia/New Zealand, China, Malaysia, Hong Kong, India, Indonesia, the Philippines, Singapore, South Korea, Taiwan, Thailand, Japan and Vietnam

§  Extensive knowledge of regulatory frameworks, best KOLs and sites across the region

§  Vast therapeutic experience including Oncology, Infectious diseases, CNS, Cardiovascular, Endocrinology, and Respiratory


Alzheimer’s Disease Clinical Trial Considerations in Asia Pacific

§  The total population of the Asia Pacific region in 2015 was estimated from United Nations data at 4.4 billion. The population aged 60 years and above was estimated at 12% in 2015.

§  The dementias are a group of diseases characterised by loss of short-term

memory, other thinking (cognitive) abilities and daily functioning.

§  Alzheimer’s disease and vascular dementia are the most common types of dementia.

§  The number of those with dementia was forecasted to increase in the Asia Pacific region from 13.7 million people in 2005 to 64.6 million by 2050.


PREVALENCE AND INCIDENCE, ASIA PACIFIC 2005 2020 2050

‘000 people

Prevalencece

Incidence

Prevalence

Incidence

Prevalence

Incidence Australia 195.4 60.2 301.3 91.1 664.1 199.7 China (inc Macao) 5,541.2 1,721.0 9,596.3 2,916.7 27,004.4 8,269.0 Hong Kong SAR 59.7 18.5 109.2 32.6 332.0 99.6 India 3,248.5 1,026.8 5,541.8 1,714.4 16,290.1 4,974.6 Indonesia 606.1 191.4 1,016.8 314.1 3,042.0 932.0 Japan 1,871.2 570.2 3,251.3 983.4 4,873.1 1,417.7 Malaysia 63.0 20.1 126.8 39.0 453.9 138.8 New Zealand 38.2 11.8 54.6 16.6 117.6 35.5 Pakistan 330.1 107.3 566.6 179.3 1,916.2 584.3 Philippines 169.8 54.8 316.3 99.2 1,158.9 353.9 Singapore 22.0 6.8 52.6 15.7 186.9 56.7 South Korea 246.3 75.5 542.2 164.3 1,569.9 475.4 Taiwan 138.0 43.1 253.4 76.6 659.3 199.4 Thailand 229.1 71.4 450.2 137.2 1,233.2 377.0

Total region 13,703.6 4,282.1 23,727.1 7,262.3 64,641.5 19,687.3


Singapore §  Prevalence of dementia and cognitive disorders to increase rapidly over the coming

years. Fast ageing population with 15-20% of the total population above the age of 65 by year 2030.

§  At the present time about 25,000 patients have dementia and this number is set to increase to 53,000 by 2020 and by 2050 the projected figure will further increase to 187,000.

§  The Ministry of Health provides clinical guidelines for Alzheimer's, and support care funding through the Care Liaison service, a central body established to coordinate and facilitate the placement of elderly sick to step-down services (nursing homes & chronic sick facilities).

§  In the later stages of Alzheimer’s disease, the patient may not be aware of the consequences of the illness and it would then be a family decision to get him/her assessed and investigated. Treatment would mostly be based on the symptoms observed and arrangements have to be made for the long-term care of the individual by way of providing for care-givers, especially if there are none in the family.


Singapore (Continued)

§  In their clinical guidelines, health authorities in Singapore recommend two groups of drugs: one (Cholinesterase inhibitors) to help improve the ability to think, understand, and remember; another group of drugs is also sometimes used in Alzheimer's disease to help with behavioral problems associated with Alzheimer's disease, such as aggressiveness, agitation, depression, and anxiety.

§  Potential clinical sites in Singapore are:

1. Singapore General Hospital Geriatric Medicine Department, Memory Clinic

2. Tan Tock Sing Hospital Geriatric Medicine Department

3. Changi General Hospital Geriatric Medicine Department

4. National University Hospital Neurology department


Taiwan §  According to available data, 10.63% of the population in Taiwan is older adults, and 4.8% of older

adults have dementia.

§  Around 110,000 Taiwanese suffer from Alzheimer's disease and other degenerative disorders, according to a survey released by the Taiwan Alzheimer's Disease Association. Alzheimer's disease causes 60-70% of all cases of dementia.

§  The healthcare system is well organized to take care of Alzheimer’s patients, either in hospitals, where patients are treated in outpatient and inpatient service from neurobiology and psychiatry departments, or in nursing homes, or in long-term care facilities.

§  The standard therapy available in Taiwan includes medications covered by health insurance if the patient meets the criteria:

• Acetylcholinesteraseinhibitor, AChEI: Aricept, donepezil, Exelon,rivastigmine, Reminyl, galantamine

• NMDA receptor antagonist: Ebixa, memantine, Witgen,memantine • Antipsychotics • Antidepressants •  Cognitive therapy, reminiscence therapy, music therapy and art therapy.


Taiwan (Continued)

§  There are 4 leading neurologists in the field of Alzheimer's disease in Taipei, Taiwan. They have good patient population at their site and they have experience in several clinical trials.

1. Dr. Jong-Ling Fuh / Taipei Veterans General Hospital 2. Dr. Chin-Chang Huang / Chang-Gung Medical Foundation - Linkou branch 3. Dr. Yu-Wan Yang / China Medical University Hospital 4. Dr. Chiung-Chih / Chang Chang Gung Memorial Hospital, Kaohsiang

§  We can safely assume that there are other sites based outside Taipei that can also be involved and offer a solid patient potential.


Korea §  Up to 10% of the elderly in Korea suffer from dementia. Further, prevalence estimates of

Alzheimer's disease range from 4.2% to 9.0%. Annual incidence rates for Alzheimer's are 2.7% to 3.4%. Thus major mental disorders are already prevalent among the Korean elderly and are likely to increase rapidly.

§  The healthcare system is well organized to take care of Alzheimer’s patients:

Primary Care: Private Clinic Most potential patients visit private clinics. If they are suspected to be diagnosed with dementia, the clinic’s doctor refers patients to either general hospitals (3rd healthcare hospital defined by government medical law) or middle hospitals (2nd healthcare hospital defined by government).

Public Health Centers 25 Dementia Centers are operating as Dementia Program in Seoul City. Preventing program & education and dementia health exams are conducted in these centers. Dementia Patients are registered into the Dementia Registry database managed by Seoul City. Dedicated doctors are working in the centers. Other provinces are in charge of public Health Centers.

General Hospital If dementia medication or cognitive activities are necessary for the patients, they are referred to the General Hospital. The following have a specific Center of dementia or Parkinson Disease in Seoul: Samsung Medical Center, Asan Medical Center, Severance Hospital, Seoul National University. Other provinces have a specific center in National University Hospital.


Korea (Continued)

§  The standard therapy in Korea includes the following medication, which should be taken by patients within 2 years after diagnosis:

• Antioxidant, NSAID, Hormone Therapy e.g. estrogen, NMDA antagonist + ChEI or memantine

• For Mild – plus cognitive disorder Tacrine or Donepezil(Aricept Tab) is given to the patient.

• For Mild to Moderate: Tacrine, Donepezil, Rivastigmine (Patch or Oral), Galantamine

• BPSD’s sign: antidepressants, antipsychotic drug, Mood Stabilizer is given to the patient.

§  The standard therapy should also include a change of lifestyle and environment, cognitive activities & training, and behavior training.

§  Patients are also provided with a health caregiver or may use hospitalized facilities.


ClinActis CNS and AD Experience

Indication Study Title (Blinded) Study Phase

No. of sites

No. of patients

Location (Countries) Responsibilities

Client (Blinded)

Alzheimer’s Disease

A multicenter, double-blind, placebo-controlled, randomised, parallel-group phase 3 study to evaluate the safety and efficacy of XXX in patients with mild to moderate Alzheimer’s disease

III 25 202 KR, TW, SG, MY, PH, HK,

TH

PM, Reg, Monitoring

EU Pharma

Dementia A Double-Blind, Placebo-Controlled, Randomized, Parallel Group, 12-Month Safety and Efficacy Trial of XXX in Subjects with Behavioral Variant Frontotemporal Dementia

III 4 24 SG, AU Pre-study visit Asia Biotech

Progressive Supranuclear Palsy

A prospective, multicenter, randomised, double-blind, placebo-controlled, parallel groups, phase 2b/3 study to compare the efficacy and safety of XXX versus placebo in the treatment of patients suffering from Progressive Supranuclear Palsy (PSP)

III 20 30 SG, HK, KR, TW, PH, MY,

TH

PM, Reg, Monitoring

EU Pharma

Multiple Sclerosis A prospective, multicenter, randomised, double-blind, placebo-controlled, parallel groups, phase 2/3 study to compare the efficacy and safety of XXX in combination with riluzole versus placebo in combination with riluzole in the treatment of patients suffering from Amyotrophic Lateral Sclerosis (ALS)

III 30 80 SG, HK, KR, TW, PH, MY,

TH

PM, Reg, Monitoring

EU Pharma


CNS and AD Experience (Continued)

Indication Study Title (Blinded) Study Phase

No. of sites

No. of patients

Location (Countries) Responsibilities

Client (Blinded)

Brain Injury A randomized, double-blind, placebo-controlled trial to investigate safety and efficacy of XXX in patients with traumatic brain injury.

III/ IV 12 216 AU, SG, HK, PH

PM, Reg, Monitoring

EU Pharma

Multiple Sclerosis Single-centre randomized crossover open-label study of pharmacokinetics, pharmacodynamics and safety of XXX and Rebif® (Merck Serono S.p.А., Italy) after single subcutaneous administration to healthy volunteers

I 1 18 SG PM, Reg, Monitoring

EU Biotech

Multiple Sclerosis Single-centre randomized crossover open-label study of pharmacokinetics, pharmacodynamics and safety of XXX and Avonex® (Biogen Idec. Ltd., United Kingdom) after single intramuscular administration to healthy volunteers

I 1 18 SG PM, Reg, Monitoring

EU Biotech


Process in Asia Pacific when diagnosis with Dementia occurs

§  Patient will be referred by GP to specialist for further evaluation of the condition.

§  This management is mainly applicable to developed countries (like Australia, Singapore, Korea, Taiwan, Hong Kong, Malaysia) where the:

-  People are more educated and can understand etiology of dementia and would seek treatment from medical practitioner

-  People can afford the treatment in their own country with better healthcare coverage

§  For developing countries, like Indonesia, Thailand, Philippines, referral to GP might not be applicable because: -  People will think this is part of the ageing process and ignore the importance to seek

treatment.


Countries to consider for Clinical Trials in AD in Asia Pacific

§  Australia, Singapore, Taiwan, Korea, Hong Kong & Malaysia. There is currently no proven cure for MCi and dementia, hence patients and doctors are very willing to participate in drug trials.


Site Capabilities in Asia Pacific

§  We can use highly skilled and experienced sites; PI and site staffs who are currently taking part in our on-going Alzheimer study in the region. The PIs and team are well trained professionals for cognitive assessment. The team in our on-going study has no issue to perform this assessment.

§  For raters, it is also important to consider standardized training – eg: online training to ensure consistency in the assessments. Also, refresher trainings (eg: every 6 months) helps ensure raters remain updated on the trial.

§  If MRI/CT scans are required, it is best to have centralized readers. Our sites are familiar with online portal to upload scans for centralized reviewer.


Benefits of conducting AD study in Asia Pacific

§  We have good patient pools in the region, e.g. Singapore pre-screened ~800 and Hong Kong pre-screened ~1000 of patients with suspected mental disorder/dysfunction in their clinic setting within 3-6 months.

§  Less costly than US/European countries

§  Trained and experienced site personnel and CRO team


Potential pitfalls and ClinActis measures to overcome them

§  The challenge in taking consent involving family members. To overcome this, we train our site personnel on how to explain the study and keep them updated of the study status. For example, we provide newsletters and email blasts to update site personnel of the recruitment status and safety data. Also, we put up educational posters of dementia condition at the sites. These efforts help to reassure subjects and their family members.

§  Care-giver support is needed. Our current trial requires weekly blood taking. To minimize inconvenience to the caregiver, some of the sites have study nurses to visit the subjects’ homes for blood taking.

§  Patient inconvenience to attend too many hospital visits as the majority of them are elderly.


Potential pitfalls and ClinActis measures to overcome them (Continued)

§  Emotional swing in elderly person that affect the assessment of cognitive test. It is important to give subjects and their family members a sense of familiarity. Hence, sites we selected have low staff turnover and dedicated facilities. This is helpful in subject retention.

§  Patients are reluctant to draw blood too frequently, which limits the recruitment in AD studies.


ClinActis success stories in Alzheimer’s Disease

§  For the current Alzheimer’s study, recruitment is challenging because subjects are required to be above 50kg and do weekly blood taking. Nonetheless, we managed to recruit patients because of the following strategies: §  Meeting / Calls with PI and site staff before SIV to train the team on eligibility

criteria – this is to ensure that the site screens their database for eligible subjects prior to SIV. This strategy also helped us to have fast FPI.

§  Motivational visits §  Newsletters. §  Sharing of best practices among sites. Once the site recruits a patient, we would

call them to find out how they recruited the patients and share their success methodology with other sites.


Contact Us for More Information

Jared Byer, MBA US Director, Strategic Relations M: +1 913-980-0028 E: [email protected]

Case Study: Dementia

Health & Medicine

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