By,ESENE IGNATIUS ,MDBAKARI TRAORE,MD

EFFECTIVENESS OF PIRACETAM IN THE TREATMENT OF ACUTE CEREBRAL STROKE IN SUB-SAHARAN AFRICA.

Research Protocol

PLAN

• BACKGROUND AND RATIONALE• GOAL • OBJECTIVES• METHODS• ETHICAL CONSIDERATIONS

1.BACKGROUND AND RATIONALE• DEFINITION

A stroke is "neurological deficit of cerebrovascular

cause that persists beyond 24 hours or is interrupted

by death within 24 hours".(WHO,1978)

1.BACKGROUND AND RATIONALE

• EPIDEMIOLOGY

• WORLDWIDE:Ischemic stroke is the 2nd cause of mortality -100 to 200 new cases / 100000 inhabitants occur each year. (Feigin, 2005).

• Developed countries: Cerebral stroke remains the third leading cause of death and the first leading cause of long-term disability in survivors. (LEYS D,1998).

• Africa: 10% global stroke mortality (Connor , 2007 ) and 56 to 83% of these stroke patients die precociously.(SeneDiouf, 2008;Sokrab, 2002).

Cameroon and Burkina Faso: ↗important public health problem ; epidemiologic

transition ↑ communicable diseases ( hypertension and diabetes) which are both

important risk factors for the development of stroke.

1.BACKGROUND AND RATIONALE

80% of strokes 20% of stroke

TWO MAJOR CATEGORIES OF STROKE:

1.BACKGROUND AND RATIONALE

• RISK FACTORS :

Advanced Age,

Hypertension,

Previous Stroke Or Transient Ischemic Attack (TIA),

Diabetes,

High Cholesterol,

Cigarette Smoking And

Atrial Fibrillation. (Donnan, 2008)

1.BACKGROUND AND RATIONALE• AETIOLOGY Depend on the type of stroke:

∆ Thrombotic stroke: Atherosclerosis

∆ Embolic stroke: Fat, Air, Cancer Cells, Bacteria.

∆ Systemic hypoperfusion: Secondary to a cardiopathy

∆ Venous thrombosis: Cerebral venous sinus thrombosis due to

locally increased venous pressure.

∆ Intracerebral hemorrhage: commonly due to hypertension,

trauma, bleeding disorders, and vascular malformations.

1.BACKGROUND AND RATIONALE• PATHOPHYSIOLOGY

Systemic events

Cerebral Hypoperfusion→ Hypoxia → Ischaemia → Infarction

Cerebral events

Ischaemic cascade → Cerebral oedema

PATHOPHYSIOLOGY

Jr cer Bl Flow & Met.2002: 22, 1399–1419;

PATHOPHYSIOLOGY

Marc Fisher,2000

1.BACKGROUND AND RATIONALE• DIAGNOSIS:

CLINICAL BASED ON NEUROLOGIC EXAMINATION.

Neurologic deficit and Cognitive disorder

PARACLINCAL TESTS :

CT scans, MRI scans, Doppler ultrasound, and Arteriography to

determine type and subtype while blood tests together with the

imaging techniques help determine cause.

1.BACKGROUND AND RATIONALE• MANAGEMENT OF STROKE 1

Occurs at stroke or neurologic Unit

Maintenance of body homeostasis is primordial .

Rehabilitative care after intensive care to regain normal life.

Prevention of modifiable risk factors

Disability : 75% of stroke survivors ↙employability, affecting

patients physically, mentally, emotionally, or a combination of the

three.

1.BACKGROUND AND RATIONALE• MANAGEMENT OF STROKE 2

Drugs: neuroprotectors and thrombolytic agents.

There is still no treatment of proven efficacy and wide

applicability for the acute phase of the disease; and various

strategies are currently being considered, both from the point

of view of circulatory impairment (antithrombotics,

thrombolytics, etc) and from the point of view of

neuroprotection of the ischaemic brain (NMDA blocking agents,

sodium channel blockers, etc) (Ricci S, 2009).

1.BACKGROUND AND RATIONALE• PIRACETAM

Piracetam is a cyclic derivative of GABA belonging to the racetams. Its chemical name is 2-oxo-1-pyrrolidine acetamide and is a nootropic drug with neuroprotective properties.

History-1964:Piracetam was first created in Belgium by UCB

Early 1970s :approved in Europe after several clinical trials Currently it sold in over 100 countries outside the US for treating several health conditions (dementia, dyslexia, stroke, vertigo, and sickle-cell anemia )under the name Nootropil.

In the US it is sold as a dietary supplement.

1.BACKGROUND AND RATIONALE• PIRACETAM:MECHANISM OF ACTION

Exact mechanism of action unknown, & different effects have been described:

Neuroprotective effect :Restorationof neurotransmission, improvement of metabolism which is evident in the presence of hypoxia (Giurgea 1970; Schaffler 1988)

Antithrombotic effect :Improvement of microcirculation,decrease of platelet aggregation.(Herrschaft 1978;Moriau 1993).

PIRACETAM:MECHANISM OF ACTION

Marc Fisher,2000

1.BACKGROUND AND RATIONALE

PIRACETAM: Presentation:Injectable. Ampoule of 5 ml contains 1 g Piracetam (200 mg/ml).

Film-coated tablets of400 mg .

Dosage:3 - 12 grams daily .

Contraindicationo Severe Renal Impairment o Hepatic Impairment And o Age <16 Years. o Cerebral Hemorrhage o hypersensitivity to piracetam, other pyrrolidone derivatives or any of the

excipients.o First trimester for pregnant women

1.BACKGROUND AND RATIONALE

• PIRACETAM:EFFECTSPositive

Ameliorate cognitive function;language inaphasic stroke patients (Greener 2001)

The drug has been reconsidered for acute stroke treatment as well (Noble 1996).

Side Effects

Are few, usually mild and transient but usually well tolerated? Symptoms of

general excitability (anxiety, insomnia, irritability, headache, agitation,

nervousness and tremor) are occasional reported (Hakkrainen, 1978).

1.BACKGROUND AND RATIONALE RATIONALE

Cerebral stroke is a grave condition (third leading cause of death in

developed countries, and the first leading cause of long-term disability in

survivors) necessitating not only an emergency treatment to prevent

neurologic complications and death but a continuation therapy to halt and

revert the consequences of the brain damage. Piracetam has been a

molecule used for this purpose owning to its purported neuroprotective

effect but its effectiveness has not been proven. A number of randomized

controlled trials have preformed but none has provided conclusive evidence

of the effect of piracetam for acute stroke patients thus recommending

further large scale or multicenter trials for the extensive testing of the

effectiveness (Ricci, 2009).

1.BACKGROUND AND RATIONALE RATIONALE

Despite its uncertain effectiveness, benefits and high cost for the patient, it is

routinely and indiscriminately prescribed by practitioners in many developing

countries Cameroon and Burkina Faso inclusive .It is on this grounds that we

intend to carry out our multicenter randomized controlled trial to ascertain

the effectiveness so as to provide a more rational treatment for the cerebral

stroke.

Among patients with acute ischemic stoke, can piracetam given within 48

hours of the onset of stroke reduce the risk of precocious death or yield a

better outcome in terms of recovery from neurologic deficit within a month

of treatment and follow up?

2. GOAL

◊To assess the Effectiveness and the Safety of piracetam in

acute stroke patients admitted in the two university teaching

hospitals of Burkina Faso and Cameroon, in Sub-Saharan

Africa, during a period of two years, from January 2010 to

December 2011.

2. OBJECTIVES

To determine in patients with cerebral stroke:

The short term effectiveness of piracetam(Onset to 1 month)

The safety of piracetam particularly for patients with hemorrhagic stroke

Early benefits of piracetam (post stroke recuperation of neurologic function).

4. METHODOLOGY

STUDY DESIGN

• Multicenter randomized triple-blind clinical trial comparing piracetam and placebo

in the treatment of acute cerebral stroke.

STUDY SETTING

Two Stroke Units in the Capital cities of Cameroon and Burkina Faso:

• University hospitals Yalgado Ouedraogo at Ouagadougou in Burkina Faso

• University hospital of Yaoundé, in Cameroon

STUDY PERIOD

• January 2010 to December 2011

4. METHODOLOGYSTUDY POPULATION (PARTICIPANTS):

• All adult patients with CT scan confirmed stroke reporting at the Ouagadougou and

Yaoundé Stroke Units within 24-48H after the onset of cerebral stroke

necessitating medical treatment only.

Exclusion criteria

Ø Cerebral stroke >48 H after onset of symptoms related to the current episode.

Ø Past medical history of episode of stroke

Ø Cerebrovascular accident associated to other co-morbidities

Ø Patients with untestable GCS

Ø Wish not to join the study

4. METHODOLOGY• PROCEDURESelection and Randomization

• The two principal investigators will independently select and randomize

participants at the trial centers using a random sequence of allocation generated

using computer software based on tables of random digits.

• Allocation rule defined at the start of study and respected throughout the studyIntervention

Two groups of patients:

Treatment group will receive piracetam, intravenously (800 mg of piracetam two

times per day) and, orally as soon as possible (the same dosage)

Control group will receive the placebo following same protocol as for treatment

group. The blinding will be triple for the clinicians ,the patients and the statisticians

4. METHODOLOGY• PROCEDURESample size requirements

• Assume α= 5% (probability to be wrong)

• and a statistical power (1-β )= 80%;

• a one month stroke mortality rate of of 33.6 % (Rosman,1986) ;

• Previous studies claim a reduction in mortality of piracetam to 20%

• STATCAL calculations n = Total (2 centers):500 (250 cases for same controls).

• Succintly: Center 1 (Yaounde): Total 250 subjects →Cases= 125 for 125 controls

Center 2 (Ouagadougou): Total 250 subjects→ Cases= 125 for 125 controls

• All the patients meeting the criteria of inclusion who give formal consent will be included

• Assumptions:20% loss to follow-up; total patient compliance

5. OUTCOME

• Our main outcomes of interest will be death from all causes and poor outcome (that is, dead, neurologic deficit) at the end of the acute phase (one month).

• *First 72H: Mortality from any cause within the first 72H following start of treatment.

• *One week-end 4 weeks: Mortality rate and Functional status using the WFNS Score WFNS SCORE• World Federation of Neurologic Surgeons (WFNS) Score, which was first reported in 1988 and

is based on the GCS (which is in worldwide used by both nurses and physicians). • WFNS Score: I-V;

score= I representing a neurologically normal individual, and score of V representing a severely damaged/moribund patient.

EYE OPENING BEST VERBAL RESPONSE BEST MOTOR RESPONSE

4=Spontaneous 5=Oriented 6=Obeys3=To speech 4=Confused 5=Localizes2=To pain 3=Inappropriate Words 4=Withdraws1=None 2=Incomprensible 3=Abnormal Flexion

(decortications)1=None 2=Extension (decelerations)99=Untestable 1=None

GLASGOW COMA SCALE

WFNS SCORE

Total GCS ∑subcategory scoresMax = 15 (4 + 6 + 5). Min=3 (1+1+1)

The WFNS Score combines GCS & neurologic deficit.

5. OUTCOME

WFNS SCORE GCS* NEUROLOGIC DEFICIT

I 15 No motor deficit

II 13-14 No motor deficit

III 13-14 Any motor deficit or aphasia

IV 7-12 With/without motor deficit

V 3-6 With/without motor deficit

99 UNTESTABLE Not testable

6. DATA COLLECTION AND ANALYSIS

The collection of the data will envisage avoiding or minimizing

any bias. Other concerns will be related to the summary of

the characteristics of the treatment group and the control

group, the specification of the primary and the secondary

data analyses for the physicians and the nurses involved in the

study, any subgroup analyses, the selection of the analytic

methods, the decision about how to handle missing data in

the analysis, how to interpret the results for “their

importance”

7. ETHICAL CONSIDERATIONS

• Permission from the Committee of Ethics of the Ministry of Health

• Formal consent from the participants or their close relative sought for their

participation to the study.

• The Respect of their confidentiality as well as the warranty of their anonymity

during the data collection and analysis proceeding, and also at the publications of

the results of the study.

8. TRIAL MANAGEMENT

The trial management is a relevant issue and will envisage in this study :

Strick monitoring and the follow- up of the patients involved ,

The measurements of the outcomes,

The handling of the loss to follow up,

Check for adverse effects

as well as the respect of patients’ privacy.

SUMMARIZE

• PROBLEM/PATIENTS: Effectiveness of Piracetam/ Cerebral Stroke patients

• INTERVENTION:Treatment with Piracetam

• COMPARISON:Placebo

• OUTCOME:Death,Neurologic Deficit

• STUDY:Multicenter Triple-Blinded Randomized Clinical Trial

Cameroon &Burkina Faso

• THANK YOU FOR YOUR KIND ATTENTION