Determining the clinical profile of Parkinson’s disease ...emra-collaborative.org/onewebmedia/EGYPD-1 Study Protocol Version... · Movement Disorder Unit, Neurology department Faculty

Clinical Study Protocol Egyptian Parkinson's Disease Study Group

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Clinical Study Protocol

Determining the clinical profile of Parkinson’s disease among Egyptian

population; A National, Cross sectional, Collaborative Study

Egyptian Parkinson's Disease Study Group

EMRA student-led national research collaborative

Final protocol

Version no.1

Date of release 17/04/2017

Contact information

Website: www.emra-collaborative.org

FB group: https://www.facebook.com/groups/EMRA.Neuro1/

E-mail 1: [email protected]

E-mail 2: [email protected]

Tel 1: +20 1090032210

Tel 2: +20 1125549087

http://www.emra-collaborative.org/

https://www.facebook.com/groups/EMRA.Neuro1/

mailto:[email protected]

mailto:[email protected]


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Principal investigator Ahmed Negida Faculty of Medicine, Zagazig University Tel: +201125549087 Email: [email protected]

Co-Principal investigator Ahmed Elgebaly Faculty of Medicine, Al-Azhar University

Hussien Ahmed Faculty of Medicine, Zagazig University

Dr. Abdelrahman Ibrahim Abushouk, MBBCh Faculty of Medicine, Ain Shams University

Lead coordinators Mahmoud Atef Morsi Faculty of Medicine, Menoufia University Tel: +201090032210 Email: [email protected] Dr. Safwat Alnahrawy, MBBCh Faculty of Medicine, Tanta University Email: [email protected]

Electronic data managers Bilal Mansour Faculty of Medicine, Al-Azhar University Email: [email protected]

Dr. Mohamed Ahmed El-hendy, MBBCh Faculty of Medicine, Al-Azhar University, Cairo

Senior supervisors (alphabetically) Dr. Ali S Shalash, MD, PhD Movement Disorder Unit, Neurology department Faculty of Medicine, Ain Shams University

Prof. Hatem Samir, MD, PhD Movement Disorder Unit, Neurology department Kasr Al-ainy school of Medicine, Cairo University

Dr. Mohamed Abdel-Daim, PhD Pharmacology department, Faculty of veternary Medicine, Suez Canal University Member of the national ethics Committee – Academy of Scientific Research and Technology

Dr. Shaimaa Eljafary, MD, PhD Movement Disorder Unit, Neurology department Kasr Al-ainy school of Medicine, Cairo University

Dr. Wael Mohamed, MD, PhD Neuroscience research unit, Pharmacology department, Faculty of Medicine, Menoufia University


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Local Coordinators

Ain Shams University Doaa Alaa

Tel: +201115042512

Email: [email protected]

Alexandria University Mohamed Mamdouh Eissa

Tel: +201276590881


Al-Azhar University (Cairo) Dr. Attia Mohamed Attia, MBBCh

Tel: +201098886071


Al-Azhar University (Cairo) Females Asmaa Sameh Rashwan

Tel: +201019740159


Al-Azhar University (Damietta) Doaa Emadeldin

Tel: +201028420048


Al-Azhar University (Assiut) Aly Mogheeth

Tel: +201097002730


Assiut University Muhammad Shawqi

Tel: +20 1100671067


Beni Suef University Randa Nabil Abdelazeem

Tel: +201208538058


Kasr Al-ainy School of Medicine Mariam Bakr

Tel: +201157890439


Mansoura University Osama Abunar

Tel: +201121274792


Menia University Hesham Mohamed Ali

Tel: +201116633496


Menoufia University Mohamed El-Semany

Tel: +201065554243



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Misr University of Science and Technology Ahmad Ali Hassanen

Tel: +201091716876


October university Omar Mohamed El Zahar

Tel: +20 1090600068


Suez Canal University Salma Fala

Tel: +201021040375


Tanta University Dr. Shorouk El mesery, MBBCh

Tel: +201092365711


Zagazig University Dr. Osama Mokhtar, MBBCh

Tel: +201143132442



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1. Working Teams

This multicenter study will be delivered using a collaborative network model.

The study teams are divided into three groups:

1.1. Steering committee

This team will be responsible for study concept and design, protocol writing,

study dissemination, Redcap system and monitoring the study, performing the

analysis and drafting the final manuscript.

1.2. Local Leaders

This team will be responsible for gaining ethical approval from their

anticipated institution, organize working teams to prevent overlapping and

monitoring the study on their level.

1.3. Data collectors

This team is composed of all collaborators who collect the data for the study;

they are the most vital part. Each team is composed of two students. Each

hospital has at least one neurologist as a supervisor to help working teams

access hospital data and ensure data accuracy.

2. Authorship

The final manuscript will be published in an international peer-reviewed

journal using the group name “Egyptian Parkinson’s disease group” as a single

author and all collaborators will gain PubMed citation under the group name

as “non-author contributors”. The contribution of all collaborators will be

described in the acknowledgment. Following publication of this project, the

identified patient data will be made available on a public portal to allow for

secondary analyses.


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3. Abstract

Introduction Parkinson's disease is the second most common

neurodegenerative disorder affecting about 1-3% of population above 50

years. The epidemiology of PD is variable from a population to another due to

the implication of multiple genetic, environmental, and dietary factors in the

pathogenesis and course of the disease. The aim of this study is to investigate

the epidemiological and clinical features of PD among Egyptian population.

Methods and analysis This is a multicenter, national, cross-sectional study.

Any hospital in Egypt performing routine follow up of PD, and any patient with

Parkinson's disease according to the UK brain bank diagnostic criteria is

eligible to enter the study. Investigators will collect observational data on PD

patients for a 3-week period during a 6-month window. The primary outcomes

of the study are pattern of early symptoms of the disease, Unified Parkinson's

disease rating scale (UPDRS) part III, and quality of life of PD patients. The

secondary outcomes include non-motor symptoms, drug sufficiency, and

caffeine consumption.

Ethics and dissemination Centers will process the required ethical approvals

from the corresponding ethics committee or institutional review board. An

oral informed consent will be taken from each patient in the presence of a

third party. During the study, patient IDs and will be kept secure. Following

the study, the deidentified IPD will be shared upon request with other

investigators to allow for secondary analyses.

Study registration The protocol of this study was registered on

www.clinicaltrials.gov (Registration number: NCT02785510).

Keywords Parkinson's disease, Clinical profile, Population, Egypt

http://www.clinicaltrials.gov/


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4. Introduction

Parkinson’s disease is the second most common neurodegenerative disorder,

affecting >1% of population above 60 years. The cardinal pathological features

of Parkinson’s disease are death of dopaminergic neurons and the formation

of Lewy bodies [1]. The diagnosis of PD depends on the presence of one or

more of the four most common motor symptoms including (rigidity, tremors,

postural instability, and bradykinesia) [2]. In addition, PD patients experience

a variety of non-motor symptoms such as anxiety, depression, mood swinging,

dementia, sleep disturbances, psychosis, hallucinations and orthostatic

hypotension [3, 4]. To date, there is no cure for PD and current

pharmaceutical therapies only target symptomatic relief.

Studying the epidemiology of PD plays a key role, not only in health care

planning, but also as a tool to investigate the cause and risk factors of the

disease. The incidence rate of PD (per 100,000 person-years) in the Unites

States is 12.3 persons and it increases to 44 persons among population over

50 years [5]. The prevalence of PD in Africa is 160 per 100,000 people and is

expected to increase by 200% within two decades after 2005 if the population

structure follows the current predictions [6].

The Egyptian population is demographically characterized by large family units

and high rates of birth and consanguinity marriage. Former studies on Arab

and North African populations showed that such demographic structure can

increase the risk of familial PD, both autosomal dominant and autosomal

recessive types. Moreover, as a developing country, the population is aging at

a faster rate than the developed countries, with an expected three-time

increase in the elderly population within the next 40 years. Therefore, the

burden of PD will increase, probably beyond the capabilities of the Egyptian

healthcare system.

There is a documented association in the literature between exposure to

pesticides and the risk of PD. Being an agricultural country, about 120,000

Egyptian citizens are annually involved in spraying 10 to 60 thousand tons of

pesticides in cotton fields, mainly in May, July, and September. These

individuals are employed by the Egyptian ministry of agriculture and they are

usually unequipped with the proper knowledge on safe handling of such

chemicals. Moreover, household use of insecticides and rodenticides

https://en.wikipedia.org/wiki/Postural_instability


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increases the exposure to organophosphates and carbamates among Egyptian

citizens.

Despite these genetic and environmental risk factors, few former studies were

published about the prevalence of PD in some Egyptian governorates and

districts. Therefore, we designed this study to investigate the clinical profile of

PD among Egyptian patients on a nationwide scale.

5. Aims and objectives

The aim of this study is to determine the epidemiological and clinical features

of Parkinson’s disease among the Egyptian population.

The primary objectives of this study are:

▪ To determine early symptoms of Parkinson's disease onset in Egyptian

population

▪ To measure the quality of life in PD patients within Egypt

The secondary objectives of this study are:

▪ To estimate the prevalence and pattern of caffeine intake in Egyptian

population with PD

▪ To investigate the association between caffeine intake and age at

disease onset in Egyptian population with PD

▪ To investigate the association between quality in life and treatment

sufficiency in Egyptian population with PD

▪ To investigate the association between caffeine intake and quality of

life in Egyptian population with PD

6. Patient and Methods

This study is a national, collaborative, cross sectional study. This study is

delivered through social media and professional networks within Egypt. We

use the collaboration methodology to enroll potential centers to perform this

study.

6.1. Study setting

This study will be conducted in self-selected (registered) centers. Eligible

center is defined as a university hospital, teaching hospital, governmental or


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private clinic, where PD patients are attending for treatment and follow up.

Eligible centers should be registered on the study website before 1st, July 2017

(see appendix).

6.2. Study population

The target population is defined as patients with Parkinson's disease, those

who meet the Parkinson’s disease diagnostic criteria of UK Parkinson's Disease

Society Brain Bank [7]. Patients, who meet these criteria, within the registered

centers are included in this study.

6.3. Exclusion criteria

We will exclude patients with the following conditions:

▪ Patients with vascular Parkinsonism (history of stroke)

▪ Patients with treatment induced Parkinsonism

▪ Patients with a history of exposure to the dopaminergic neurotoxin

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)

6.4. Data entry

Data will be submitted to the Research Electronic Data Capture (RedCap)

system of Al Azhar University, Egypt (http://redcap.medicineazhar.edu.eg).

Each collaborating team will be assigned unique username and password to

access RedCap system. Data collection is designed to allow entry of individual

patient data electronically and uploading a scan of the data collection forms.

Data will be double-checked by the steering committee to avoid data entry

errors.

6.5. Study variables and outcome measures

We will collect the following data variables and measures from each eligible

patient:

▪ Age at disease onset

▪ Time to diagnosis

▪ Initial motor symptom

▪ Side of initial motor symptoms

▪ Clinical subtype of the disease

▪ Pattern of levodopa treatment

▪ Levodopa equivalent dose per day

http://redcap.medicineazhar.edu.eg/


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▪ Duration of levodopa treatment from disease onset

▪ Non-motor symptoms measured by the non-motor symptoms

questionnaire

▪ Quality of life including mobility, activities of daily living, emotional

well-being, stigma, social support, cognition, communication, and

bodily discomfort. The Parkinson's disease quality of life

questionnaire (PDQ-39) will be used.

▪ Caffeine consumption measured by the Caffeine use questionnaire

developed by Millar and colleagues.

▪ Motor functions measured by the Unified Parkinson's disease rating

scale – Part III will be included (if available)

6.6. Statistical analyses and power calculation

Assuming the recruitment of 15 patients within a 3-week period from 30

centers. This will give a total of 450 patients, which allows for detecting a

5(±3)% rate of early disease symptoms in the population with a confidence

level of 95% and 5% margin of error.

Data will be presented as mean and standard deviation for continuous

variables and frequencies and percentages for categorical variables. Data

normality will be examined using the Kolmogorov-Smirnov test. Chi-square

test and student t-test will be employed the test the significance of

differences in categorical and continuous variables, respectively. Multivariate

analysis will be conducted to compare caffeine consumption and quality of life

in PD patient groups (classified according to early disease symptoms). An

alpha level below 0.05 will be considered for statistical significance. Statistical

analysis will be conducted using Stata statistical package (version 14) for

windows.

7. Discussion

In this protocol, we have presented the detailed design and objectives of our

cross-sectional study, targeted at nationwide assessment of the clinical profile

of PD among the Egyptian population. The definition of study population, the

ethical soundness of the protocol, and the means for data collection were

given attention in the design process. Moreover, we reported the exact

methods of data entry and provided prospective solutions for possible

challenges in our statistical analysis.


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In a systematic review by Benamer et al. (2008) on the clinical profile of PD

among Arabs, the authors found only three epidemiological studies,

conducted in Tunisia, Libya, and Saudi Arabia. The review reported that PD

has an incidence of 4.5 per 100,000 person-years, with a prevalence that

ranges from 27 to 43 per 100,000 persons. It concluded that the clinical

features of PD in Arabs are not different from those reported in other

populations and highlighted the need for further epidemiological studies on

PD clinical profile within Arab populations.

After surveying the literature, we identified four epidemiological studies,

recently published from Egypt, on the epidemiology of PD. In 2012, Khedr and

colleagues conducted a community-based survey in Assiut governorate, Egypt

to identify the prevalence and clinical profile of PD within the Egyptian

population. The authors estimated a crude prevalence of 659/100,000

inhabitants, which increases with age, living in rural areas, and illiteracy.

Moreover, the study showed that compared to other populations, these

patients showed a high prevalence of mood/cognition dysfunction (84.4%)

and gastrointestinal symptoms (90.9%).

Another two cross sectional studies by El-Tallawy et al. (2013) and Khedr et al.

(2015) were conducted on the Egyptian population in the New Valley and

Qena governorates, respectively. These studies have reported crude

prevalence rates, ranging from 213.15 to 2748 per 100,000 individuals. These

figures are relatively high, compared to those, reported in other Arab

countries. Khedr et al. explained their findings by the presence of several

sugar refining, paper making, and manganese production factories in Qena

governorate, which partly drain their sewage into the Nile or its water canals.

Excessive deposition of manganese within the brain tissue leads to

manganism, a condition that shares multiple features with PD such as

hypokinesia, rigidity, and psychotic symptoms. Table 1 shows a list of the

cross-sectional studies, conducted within the Arab populations, on the

epidemiology or clinical profile of PD.


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Table 1 shows a summary of epidemiological studies on Parkinson's disease

patients among the Arab population.

Study ID/ Country Screening Method PD Diagnostic approach

Number of cases

Total population

Prevalence (per 105 persons)

Khedr et al. 2012 (Assiut governorate – Egypt)

Door to door study with face to face interviews

The UK Parkinson’s Disease Society Brain Bank Criteria

39 6478 557

El-Tallawy et al. 2013 (New Valley governorate- Egypt)



33 62,583 213.15

El-Tallawy et al. 2013 (Red Sea governorate- Egypt)


World Health Organization Diagnostic Criteria

Not reported

33,283 452.1

Khedr et al. 2015 (Qena governorate Egypt)



44 8027 548

Al Rajeh et al. 1993 (Saudi Arabia)


Presence of 2 of the 4 cardinal symptoms: Rigidity, hypokinesia, resting tremors, and postural instability.

6 23,227 27

Romdhane et al. 1993 (Tunisia)

Interview questionnaire

Not reported 15 34,874 43

Ashok et al. 1986 (Libya) Not reported

Presence of 2 of the 4 cardinal symptoms: Rigidity, hypokinesia, resting tremors, and postural instability.

163 518,745 31.4

Masalha et al. 2010 (Arab Israel)

Drug-tracer

Patients on anti-parkinsonian medications with further examination by neurologists.

49 115,000 43.24


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Another focus of our study is the assessment of non-motor symptoms (NMS)

among the Egyptian PD patients, including cognitive impairment, sleep

disturbances, neuropsychiatric disorders, sexual dysfunction, and

gastrointestinal and cardiovascular symptoms. These symptoms can limit the

effective treatment of motor manifestations; therefore, early management of

NMS can supplement motor treatment, limit the financial impact of PD, and

improve the quality of life for the patient and the caregiver. In our study, we are

planning to use the Non-Motor Symptoms Scale (NMSS), which was designed to

quantify the overall prevalence of NMS.

Other important characteristics of PD that were not comprehensively

investigated in Egyptian patients include the mean age at disease onset, time to

PD diagnosis from the onset of symptoms, drug responsiveness, and quality of

life. Therefore, in our study, we planned to identify these variables by using

validated questionnaires such as the Parkinson's disease quality of life

questionnaire (PDQ-39) and calculating the duration of Levodopa treatment and

its current dosages.

7.1. Expected challenges and solutions

The presence of cognitive impairment in some parkinsonian patients may

increase the risk of recall bias; therefore, during the interviews, caregivers will

be allowed to help their patients to ensure accurate data collection. To increase

the participation of clinical neurologists in data collection, all practicing

neurologists who contribute to data collection will be listed as collaborators in

our published study. All used questionnaires or scales of assessment will be

prospectively reviewed by expert neurologists and all open-ended questions will

be coded and entered in a simple spread sheet. We excluded patients with

vascular or treatment-related Parkinsonism due to the temporary nature of the

condition.

In summary, there are no sufficient data about the clinical profile of PD in Egypt.

Therefore, we designed this nation-wide, cross sectional study to provide these

data, which would provide better therapeutic management for PD patients and

guide future planning of healthcare services in Egypt.


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8. Ethical Considerations

8.1. Risk, benefit, and participant confidentiality

The Study does not have any physical, psychological, social, legal, economic, or

any other anticipated risks to study participants. In addition, participants will not

receive a direct benefit from the study. Investigators will keep the privacy of

patient data. Data submitted to the RedCap will not include patient name or

national ID; instead, patient ticket number will be used as a unique number to

avoid duplicate reporting of the patient data. We confirm that patient data will

not be used outside this study.

8.2. Informed Consent Process

We will comply with institutional guidelines of each registered center. The

informed consent form, provided by the anticipated IRB or ethics committee,

will be used by study collaborators. All eligible patients who agree to participate

in the study will be asked to sign the informed consent.

8.3. Institutional Review Board

Before starting data collection, collaborators of the registered centers should

gain ethical approval from the anticipated local IRB or ethics committee of their

institution. Investigators are advised to comply with institutional guidelines. In

case of any changes to the study protocol, the ethics committee will be

informed.

9. Publication and dissemination

This project will be published using a collaborative publishing model. The final

manuscript will be published in an international peer-reviewed journal using the

group name “Egyptian Parkinson’s disease group” as a single author and all

collaborators will gain PubMed citation under the group name as “non-author

contributors”. The contribution of all collaborators will be described in the

acknowledgment. Following publication of this project, the identified patient

data will be made available on a public portal to allow for secondary analyses.


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10. Centers registration

This study follows a collaborative model. Collaborators are required to register

their centers and submit the institutional ethical approval before starting data

collection.

This study will be published using the collaborative published model. The

manuscript(s) are published under a single group name as an author (Egyptian

Parkinson’s Disease Study Group). and all collaborators (see the working teams

in the next section) will be listed with their institution in the acknowledgment

section.

11. References

1. Obeso JA, Rodríguez-Oroz MC, Benitez-Temino B, et al (2008) Functional organization of the basal ganglia: Therapeutic implications for Parkinson’s disease. Mov Disord 23:548–559. doi: 10.1002/mds.22062

2. Jankovic J (2008) Parkinson’s disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 79:368–376. doi: 10.1136/jnnp.2007.131045

3. Zindo FT, Barber QR, Joubert J, et al (2013) Steady progress on parkinson’s disease. Eur J Med Chem 54:883–891. doi: 10.1016/j.bmcl.2010.07.013

4. Ceravolo R, Frosini D, Rossi C, Bonuccelli U (2010) Impulse control disorders in Parkinson’s disease: definition, epidemiology, risk factors, neurobiology and management. Park Relat Disord 15:S111–S115. doi: 10.1016/S1353-8020(09)70847-8

5. Van Den Eeden SK (2003) Incidence of Parkinson’s Disease: Variation by Age, Gender, and Race/Ethnicity. Am J Epidemiol 157:1015–1022. doi: 10.1093/aje/kwg068

6. Dotchin C, Msuya O, Kissima J, et al (2008) The prevalence of Parkinson’s disease in rural Tanzania. Mov Disord 23:1567–672. doi: 10.1002/mds.21898

7. Hughes AJ, Daniel SE, Kilford L, Lees AJ (1992) Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55:181–184.

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Determining the clinical profile of Parkinson’s disease ...emra-collaborative.org/onewebmedia/EGYPD-1 Study Protocol Version... · Movement Disorder Unit, Neurology department Faculty