Protocols

TESPI (Thrombolysis in Elderly Stroke Patients in Italy):

a randomized controlled trial of alteplase (rt-PA) versus
standard treatment in acute ischaemic stroke in
patients aged more than 80 years where thrombolysis is
initiated within three hours after stroke onset
Svetlana Lorenzano*, and Danilo Toni for the TESPI trial Investigators

Rationale Intravenous (i.v.) thrombolysis with recombinant

tissue-Plasminogen Activator (rt-PA) (alteplase) within three
hours from symptom onset is the only approved treatment
of pharmacological revascularization in acute ischaemic
stroke. However, the current license limits the use of rt-PA to
patients aged 80 years due to the lack of evidence of safety
and efficacy of this treatment in the elderly from randomized clinical trials. This article describes the design of the
Thrombolysis in Elderly Stroke Patients in Italy (TESPI) trial
planned to fill the lack of controlled data on i.v. thrombolysis
in this age category of stroke patients.
Aims To collect efficacy and safety data on i.v. alteplase
(rt-PA) in patients aged more than 80 years, to demonstrate
that the treatment of these patients within three hours of
symptoms onset of an acute ischaemic stroke with i.v. rt-PA,
compared to patients receiving standard treatment (according to the national guidelines), will result in an improved
clinical outcome with a favourable benefit/risk ratio.
Design TESPI is a prospective, multicenter, national, openlabel, controlled (non-treated group as control), randomized,
parallel group trial with blinded evaluation of outcome in
patients older than 80 years treated with i.v. rt-PA within
three hours after ischaemic stroke onset. The randomization
procedure assigns patients to the treatment group with
IV alteplase (09 mg/kg of body weight) or to standard

Correspondence: Svetlana Lorenzano*, Unit di Trattamento

Neurovascolare, Department of Neurological Sciences, Policlinico
Umberto I Sapienza University, Viale del Policlinico 155, 00161 Rome,
Italy.
E-mail: svetlana.lorenzano@uniroma1.it
Conflict of interest: None declared.
Funding: TESPI is a non-profit study and it was approved and funded by
AIFA Agenzia Italiana del Farmaco (Italian Medicines Agency, for the
Drug approval and vigilance), with the protocol number FARM65KNKY.
DOI: 10.1111/j.1747-4949.2011.00747.x

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treatment group with a 1 : 1 basis. A three-month follow-up,

when applicable, is performed by a blind assessor. Six
hundred patients will be enrolled (300 patients per arm) The
study period has been planned to be of three years.
Study Outcomes The primary efficacy end-point is the disability at day 90, dichotomized as a favourable outcome
(modified Rankin Scale 02) or unfavourable outcome (modified Rankin Scale 36). The main primary safety end-point
is symptomatic intracerebral haemorrhage defined as any
hemorrhage at the 2236 h post-treatment scan combined
with neurological deterioration leading to an increase of
one or more points at the National Institutes of Health
Stroke Scale. The TESPI trial, with the protocol number
FARM65KNKY, is registered in the European Union Drug
Regulating Authorities Clinical Trials database with the
number 2007-006177-88 and in the Stroke Trials Registry of
the Washington University Internet Stroke Center.

Key words: elderly, intravenous thrombolysis, ischaemic

stroke, rt-PA

Introduction
Thrombolysis with intravenous (i.v.) rt-PA administered
within three hours of symptom onset is the only proven effective pharmacological reperfusion treatment for acute ischaemic stroke. The current license defined strict eligibility criteria
which limit the use of rt-PA to patients aged 80 years. This is
properly due to the lack of clear evidence of safety and efficacy
of this treatment in the elderly as most randomized clinical
trials (RCTs) on thrombolysis in acute ischaemic stroke arbitrarily excluded or underrepresented patients over 80 years,
having frequently empirically fixed age limit of 80 years. The
likely reasons for this exclusion are several: the highest prevalence in the elderly patients of comorbidities with relative
contraindications to thrombolysis, their presumed poorer
outcome, and major risk of symptomatic intracerebral haemorrhage (SICH) occurrence that could outweigh the benefits

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of the therapy. But the incidence of stroke increases exponentially with age (1). Life expectancy has increased over the past
few decades, and the elderly is the fastest-growing component
of the population worldwide and particularly in the Western
world, and it is expected to further increase in the next few
years. Moreover, age is an important independent predictor
for poor outcome after ischaemic stroke, and among older
patients, there is a larger proportion discharged to long-term
institutional care, with relevant financial implications on both
health and social care system. For all these reasons, this subgroup of patients might benefit more from thrombolysis.
Hence, safe implementation of this therapeutic approach even
in the elderly would be an issue of great relevance for which
clearer data are urgently required.
No evidences from RCTs on the efficacy/safety ratio of i.v
thrombolysis in elderly patients are available. The Neurological Institute of Neurological Disorders and Stroke (NINDS)
rt-PA Stroke Trial (2) part I had an age limit that was subsequently removed in the second part of the study. Since then,
only 42 patients over 80 years of age were included, and no
comparison with younger patients was performed. Analysis of
data from NINDS trial reported the efficacy of rt-PA for acute
ischaemic stroke regardless of the subgroups, and, therefore,
no threshold value for age was identified (3). Most of phase IV
studies on thrombolysis (4) included elderly patients without
an age limit. None, however, stressed specifically the issue of
the thrombolytic treatment in the elderly.
In the last few years, some open studies on i.v. thrombolysis
have addressed the issue of treatment in older patients, with
controversial results (513). In a few studies, the older patients
were less likely to recover favourably as compared with the
young patients (6,912). In other studies, there was no difference among age groups (5,7,8,13). A recent systematic review
(14) selected some of these cohort studies collecting data on
2244 patients, of whom 477 (ranging from 12 to 31% in the
different studies) were aged 80 years. All these studies have
discrepancies due to the lack of homogenous baseline characteristics between the two age groups, and, furthermore, the
definition of SICH varied among the studies. Therefore, these
studies do not allow to draw any conclusion about the safety
and effectiveness of thrombolysis in the elderly. However, they
seem to suggest that older patients have less likely a favourable
functional outcome (odds ratio (OR) 053; 95% confidence
interval (CI) 042066, P < 0001), a higher mortality rate
(OR 309; 95% CI 237403; P < 0001), and similar risk of
SICH (OR 122, 95% CI 077194; P = 034) as compared to
younger patients. Data from an Italian cohort of patients confirmed these results (13), showing a threefold higher mortality
(341% vs. 106%, P < 0001), a non-significantly lower rate of
three-month good outcome (modified Rankin Scale (mRS)
02) (44% vs. 585%, P = 0897), and the same rate of SICH
(both non-fatal and fatal) (48% vs. 48%) in the elderly compared to younger patients. The results would indicate an
overall beneficial effect of t-PA in the elderly group. As baseline National Institutes of Health Stroke Scale (NIHSS) was

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the only statistically significant predictor of both mortality

and poor outcome in the >80 group, the increased mortality
was not explained by a higher rate of SICH. Therefore, it is
likely that alteplase exhibits an age-independent safety profile
despite the alleged higher risk of SICH in the older patients.
It has been suggested that new neuroimaging methods could
be useful for a better and safer selection of the elderly patients
likely to benefit from thrombolysis. In fact, in a recent study,
none of the patients aged over 80 years selected by multiparametric magnetic resonance imaging (MRI) for thrombolysis
had a SICH, even if there was no decrease in the in-hospital
mortality or improvement of the clinical outcome compared
with the patients not screened with MRI (12).
All the data discussed above may be useful to understand
more about the issue of thrombolysis in the elderly, but are
neither evidence based nor conclusive. Hence, RCTs are necessary before definitive recommendations on i.v. thrombolysis
in elderly patients can be given. The Third International
Stroke Trial (IST-3) (The Third International Stroke Trial,
unpublished data) is a prospective, randomized, open-label,
blinded end-point study of rt-PA in ischaemic stroke patients
aimed at defining the risk/benefit ratio of i.v. thrombolysis
among patients who do not exactly meet the current license
criteria. Hence, the study allows inclusion of patients older
than 80 years, within a six-hour window. However, the sixhour time window will likely result in fewer patients being
treated within three-hours of symptom onset, while the evidence that the shorter the time to treatment the better the
outcome (15) might be particularly true in elderly patients.
We herein present the design of the trial Thrombolysis in
Elderly Stroke Patients in Italy (TESPI), which we planned to
hopefully fill the lack of controlled data on i.v. thrombolysis in
this age category of patients.

Objectives
The primary objective is to collect efficacy and safety data on
i.v. alteplase (rt-PA) in patients aged more than 80 years, to
demonstrate that the treatment of these patients with IV rt-PA
within three hours of symptoms onset of an acute ischaemic
stroke, compared to patients receiving standard treatment
according to the national guidelines (Stroke Prevention and
Educational Awareness Diffusion, SPREAD) (16), will result in
an improved clinical outcome with a favourable benefit/
risk ratio. The secondary objectives are: to study efficacy measures along 90 days and prognostic factors, and to set, in this
patient population, a neurological severity cut-off point, if
any, below which benefit/risk ratio of thrombolytic therapy is
advantageous.

Methods
Design
The TESPI study is a prospective, multicenter, national,
open-label, controlled (standard treatment group as control),

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randomized, parallel group trial with blinded evaluation of
outcome in patients older than 80 years treated with i.v.
rt-PA within three hours after stroke onset. An open-label
(standard treatment group as control) and not a doubleblind design (placebo group as control) was planned due to
economic reasons. The creation of the placebo, the labelling
of both drug and placebo for the double-blind design, and
the delivering to all the participating centres, also considering the study sample size, would have required additional
costs that the overall funds available for the study could not
guarantee.
All participating hospital sites received approval from local
ethics committee before initiation of the study. A patient
may be enrolled into the study after giving his/her informed
consent, which, according to national regulatory and legal
requirements, can also be confirmed by an independent
witness when the patient is not able to sign.

Patient population
Patients aged >80 years (patients aged 80 years + at least one
day will be included) presenting with acute ischaemic stroke
symptoms and being liable to be thrombolysed within
three hours after stroke onset will be enrolled. The study
is conducted at stroke units with 24-hour access to brain
computed tomography (CT). The inclusion and exclusion
criteria are similar to those of the Safe Implementation
Thrombolysis in Stroke-Monitoring Study (17). Exceptions
are the upper limits of the NIHSS score of 17 and of blood
glucose level of 200 mg/dl, above which patients are excluded
from randomization. However, blood glucose levels up to
300 mg/dl are allowed, if they can be reduced to <200 mg/dl
before treatment. Other exclusion criteria include ordinary
contraindications for thrombolysis, and they are detailed in
Table 1.

Randomization
At the baseline visit, after protocol procedures (including
medical history, physical examination, NIHSS, mRS, laboratory tests, electrocardiogram, cerebral CT scan), patients are
randomized with a 1 : 1 basis to the treatment group or to the
standard treatment group through an Interactive Voice
Response System (IVRS). All the data entered by IVRS, which
is active 24 h/7 days, are automatically transferred to the electronic Case Report Form (e-CRF). In case of technical
problem with the IVRS, the randomization procedure can be
done by connecting to the e-CRF and answering the questions
about the birth date of the patient, stroke onset date/time, and
if he/she has signed the informed consent. The system allows
to see the identification number of the patient and the treatment arm attributed.

Treatments
After randomization, patients are assigned to the investigational product or to comparator treatment. Investigat-

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ional product is alteplase while the comparator treatment is

the standard treatment, according to national guidelines
(SPREAD) (16). The study medication is administered as a
total single dose of 09 mg/kg with a maximum upper dose
limit of 90 mg. Ten per cent of the total dose is administered as
an i.v. bolus over 12 mins, while the remaining 90% of the
dose is given by continuous i.v. infusion over 60 mins if there
is no evidence of an allergic reaction within five-minutes following the administration of the test dose. Marketed drug
boxes are used and labelled with trial identification (study
code, patient number, and date of administration). The investigator may prematurely terminate the administration of
study drug for any medical reason and even patients may
prematurely terminate the study without giving any reason.
These patients, however, must be followed up for 90 days if
possible.
No specific rescue medication will be provided, but symptomatic measures should be taken for the treatment of severe
bleeding at a non-compressible site or for the reversal of fibrinolysis during study drug administration, as indicated in
previous protocols of trials with alteplase (18, International
Stroke Trial, unpublished data). Treatment of increased blood
pressure (BP) should be started if two readings five to 10 mins
apart reveal a systolic BP above 180 mmHg or a diastolic BP
above 105 mmHg.
Restrictions are established as regards concomitant medications during the first 24 h after study drug administration. Additional thrombolytic medication (e.g. urokinase or
streptokinase) is forbidden. According to national guidelines
(SPREAD) (16), low-dose subcutaneous unfractionated
heparin or low-molecular-weight heparin may be given concomitantly during the first 24 h in order to prevent deep
venous thrombosis. Intravenous heparin at any dose is forbidden before and during the study drug administration and the
initial 24 h after completion of administration of study drug.
Thereafter, i.v. heparin must not be started before the second
CT is evaluated, and reveals no signs of intracerebral bleeding.
Administration of oral anticoagulants, antiplatelet agents (i.e.
aspirin), and haemorrheologic agents is prohibited during the
first 24 h after completion of the study drug administration.
Other drug therapies may be given according to patient
needs. Osmotic agents (mannitol, glycerol) may be given if
intracranial pressure is increased.

Outcomes
Table 2 reports the study flow charts with the schedule of
clinical assessments.
Further BP and heart rate monitoring will take place in the
following order: every 15 mins until hour 2 (i.e. 15, 30, 45, 60,
75, 90, 105, 120 mins after starting the infusion of study medication), every 30 mins until hour 6 (i.e. 150, 180, 210, 240, 270,
300, 330, 360 mins), and every hour until hour 24 (i.e. seven,
eight, nine, etc. until 24 h after starting the infusion.

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Table 1 Inclusion and exclusion criteria

Inclusion criteria
Female or male inpatients
Age >80 years.
Clinical diagnosis of ischaemic stroke causing a measurable neurological deficit defined as impairment of language, motor function, cognition
and/or gaze, vision, or neglect. Ischaemic stroke is defined as an event characterized by the sudden onset of an acute focal neurologic
deficit presumed to be due to cerebral ischaemia after CT scan excludes haemorrhage.
Onset of symptoms <3 h prior to initiation of administration of study drug. Stroke symptoms are to be present for at least 30 mins and have
not significantly improved before treatment. Symptoms must be distinguishable from an episode of generalized ischaemia (i.e. syncope),
seizure, or migraine disorder.
Patient is willing to participate voluntarily and to sign a written patient informed consent. Informed consent will be obtained from each patient
or the subjects legally authorized representative or relatives, or deferred where applicable, according to the regulatory and legal requirements of the participating centres. Patients who are unable to sign but who are able to understand the meaning of participation in the
study may give an oral witnessed informed consent. These patients have to make clear without doubts that they are willing to participate
voluntarily and must be able to understand an explanation of the contents of the information sheet.
Exclusion criteria
Cerebral CT exclusion criteria:
Evidence of intracranial haemorrhage on the CT scan.
General exclusion criteria:
Symptoms of ischaemic attack began more than 3 h prior to infusion start or when time of symptom onset is unknown.
Minor neurological deficit or symptoms rapidly improving before start of infusion.
Severe stroke as assessed clinically (e.g. NIHSS > 17) and/or by appropriate imaging techniques.
Epileptic seizure at onset of stroke.
Symptoms suggestive of subarachnoid haemorrhage, even if the CT scan is normal.
Administration of heparin within the previous 48 h and a thromboplastin time exceeding the upper limit of normal for laboratory.
Prior stroke within the last 3 months.
Patients with any history of prior stroke and concomitant diabetes.
Platelet count of below 100 000/mm3.
Systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg, or aggressive management (IV medication) necessary to reduce
BP below these limits.
Blood glucose <50 or >200 mg/dl; values up to 300 mg/dl are allowed, if they can be reduced to <200 mg/dl before treatment.
Known haemorrhagic diathesis.
Patients receiving oral anticoagulants, e.g. warfarin sodium.
Manifest or recent severe or dangerous bleeding.
Known history of diagnosed or suspected intracranial haemorrhage.
Any history of central nervous system damage (i.e. neoplasm, aneurysm, intracranial or spinal surgery).
History of haemorrhagic retinopathy.
Recent (less than 10 days) traumatic external heart massage.
Recent (less than 10 days) puncture of a non-compressible blood-vessel (e.g. subclavian or jugular vein puncture).
Known current bacterial endocarditis, pericarditis.
Acute pancreatitis.
Documented ulcerative gastrointestinal disease during the last three months.
Documented oesophageal varices.
Documented arterial-aneurysm, arterial/venous malformation.
Neoplasm with increased bleeding risk.
Severe liver disease, including hepatic failure, cirrhosis, portal hypertension.
Major surgery or significant trauma in past three months.
Current or recent (within three months) participation in another investigational drug treatment protocol.
CT, computerized tomography; NIHSS, National Institutes of Health Stroke Scale; BP, blood pressure.

The clinical evaluation at day 90 is done by blinded central

assessor through a telephone interview. Besides the baseline
CT, a second scan must be performed 22 to 36 h after starting
the infusion of trial medication. Other CT scans are optional
and must be performed only in case of clinical deterioration.
Outcome measures are listed in Table 3. The primary
outcome consists in evaluating disability at day 90 dichotomized as a favourable outcome (mRS 02) or unfavourable
outcome (mRS 36). The secondary outcomes are a global

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outcome analysis combining four neurological and disability

scores. The assessment of safety, incidences, and severity of
adverse events (AEs) as per system organ class, including
mortality at day 90, stroke-related and neurological, cerebral
herniation rate, symptomatic oedema, and symptomatic cerebral bleedings, will be evaluated. Intracranial haemorrhages
will be assessed separately. SICH is defined as any haemorrhage on the 2236 h post-treatment imaging scan combined
with a neurological deterioration leading to an increase of one

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Table 2 Flow chart of trial procedures

Visit
Hour/day window

1A
Baseline (within
three hours) D0

2 h 15 min

2
24 h 1 h
D1

3
7 days 1 day
D7

x*
x*

x
x
x
x
x
x

4
90 days 14 day
D90

x
60 mins

rt-PA/standard treatment
Demographics
Medical history
Inclusion/exclusion criteria
Informed consent and
subject information
IVRS contact
Physical exam
Vital signs
Concomitant therapy
Adverse events
12-Lead EKG
CT scan
NIHSS
Glasgow outcome score
Modified Rankin Scale
Barthel index
Pat. termination record

1B
Trial drug
admin

x
x
x
x
x
x
x
x
x
x
x
x

x
x

x
x
x
x

*CT: between 22 and 36 h, NIHSS closely before or after CT. Only for patients receiving rt-PA. Optional in case of clinical deterioration. Time after
the end of infusion of study drug. Clinical evaluation by a co-investigator not involved in the acute treatment phase for a specific patient.

Table 3 Outcome measures

Primary end-points
Patients (%) with favourable outcome at day 90, according to:
modified Rankin Scale (mRS) 02
Secondary end-points
At days: 0 (2 h after treatment), 1, 7
NIHSS (total score), mean/median change from baseline
At day: 7
NIHSS: improvement of 4 points or score 01
At day 90:
mRS 01; Barthel Index 95; Glasgow Outcome Scale 12
Stratified end-point of NIHSS and mRS
Baseline NIHSS <8: mRS 0 response
Baseline NIHSS 814: mRS 02 response
Safety end-points
Patient survival at day 90
Stroke-related and neurological deaths
Adverse events recording
Cerebral herniation rate
Symptomatic oedema
Vital sign measurement
Symptomatic intracerebral haemorrhage at the 2236 h posttreatment scan combined with neurological deterioration
leading to an increase of 1 or more points on the NIHSS or
leading to death.
NIHSS, National Institutes of Health Stroke Scale; mRS, modified
Rankin Scale.

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or more points on the NIHSS or leading to death. Hemorrhagic events will be classified as haemorrhagic infarction type
I or II or as parenchymal haemorrhage type I or II (19).

Data monitoring body

A Steering Committee consisting of four neurologists is established. The Steering Committees functions include the review
of enrolment and trial conduct at the sites, recommendation
of remedial actions (if necessary), recommendation of protocol amendments, review of the results, preparation of the
scientific publication(s), and validation of the Data Safety
Monitoring Board (DSMB) charts.
In addition to the safety monitoring by the Promoters
Medical Monitors and Safety Officers, an independent DSMB
is established to periodically review all safety issues during
the course of the trial. No interim analysis is foreseen. DSMB
will give recommendations about the study conduction and
an eventual early interruption of the trial. It will review
the results of the study and evaluate the risk/benefit ratio
of the treatment. DSMB consists of one neurologist, one
neuroradiologist, and one biostatistician. DSMB periodically
receives and analyses blinded data from the Trial Data Center
and from the centralized CT reading panel. Safety reviews
are conducted on all data available on a regular basis. The
procedures and guidelines of the DSMB were reviewed by
the Steering Committee before the beginning of the trial.
The procedures for reporting the AEs are advanced and not
time consuming. All AEs, whether or not considered to be

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related to the treatment by the investigator, must be documented in the appropriate adverse event case report form
from the admission until the hospital discharge. Any serious
adverse event (SAE), whether or not considered related to
the investigational product, and whether or not the investigational product has been administered, must be immediately
reported. The SAE notification is sent electronically via email
to the Clinical Research Organization (CRO) and another
copy to the responsible of the Scientific Board, which have the
role to communicate the SAE to the Authority. Thereafter, the
Clinical Monitor must provide a written report of the AE and
any sequelae to CRO.
The e-CRF allows monitors and data managers to check
through a password all the entered data for each centre involving in the trial.
The Promoter reserves the right to discontinue this trial at
any time for failure to meet expected enrolment goals, for
safety or any other administrative reasons.

Quality assurance
A quality assurance audit of this trial may be conducted by
the Promoter or Promoters designees. The quality assurance
auditor will have access to all medical records, the investigators
trial related files and correspondence, and the written informed
consent documentation that is relevant to this clinical trial.
Therefore, case report forms, progress notes, and copies of
laboratory and medical test results must be available at all times
for inspection by the Promoters clinical trial monitor and
health authorities (e.g. European Medicines Agency, Food and
Drug Administration). The accuracy of the data will be verified
by reviewing the above-referenced documents.

Sample size
Sample size calculation is based on the following assumptions.
The proportion in group 1 (treatment group) is assumed to be
044 under the null hypothesis and 058 under the alternative
hypothesis. Group sample sizes of 280 in group 1 and 280 in
group 2 achieve 90% power to detect a difference between the
group proportions of 014 with regard to the percentage
of patients with a favourable outcome (mRS 02). The test
statistic used is the two-sample chi-square. The significance
level of the test was targeted at 005.

Statistical analysis
The primary null hypothesis of interest is that the magnitude
of response with regard to the primary end-point (mRS 02)
is not different between the two groups; the alternative is that
rt-PA is superior over non-treated group.
An intent-to-treat analyses (ITT) of all patients randomized
as well as an explanatory analyses of all patients randomized
and treated according to protocol (PP) will be carried out
considering a descriptive presentation and an exploratory

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evaluation of all efficacy data. Baseline characteristics will be

tabulated; counts and percentages for categorical data and
continuous data will be summarized by means of the following statistics: the number of observations, means, standard
deviations, median, minimum, and maximum. To assess baseline comparability of the two groups, we perform appropriate
statistical tests.
As regard the primary analyses, the ITT analyses on mRS
02 at day 90 will be carried out by the chi-square test on
proportions (alpha level 5%, two-sided). The proportion of
response rate will be estimated with 95% CI, using both traditional method and the Wilson method. Also the relative risk
(RR) will be presented. For secondary analyses, descriptive
analyses and data set exploratory, survival analyses (Kaplan
Meier), and regression analyses (Cox) will be carried out.
As regard the safety analyses, incidence and severity of AEs
will be described for all treated patients by treatment group. An
explanatory analysis of all patients randomized and treated
according to protocol will be carried out considering a descriptive presentation and an exploratory evaluation of all safety
data. This population will be fixed by the Steering Committee
under blinded conditions before database lock. All (dichotomized) safety end-points (including intracranial haemorrhages) will be analysed by chi-square test on proportions. In
addition, the RRs with 95% CIs will be presented. Furthermore,
the lower limits of the 95% CIs will be compared with the
observed RR in NINDS (2) and the combined analyses of
European Cooperative Acute Stroke Study (ECASS) II (20)
and Alteplase Thrombolysis for Acute Noninterventional
Therapy in Ischemic Stroke (ATLANTIS) (21). In general, RRs
reduction will be associated to absolute risk differences for
an overall assessment of the treatment differences; furthermore, the number needed to treat (the number of patients
who need to be treated to prevent one adverse outcome) will
be evaluated. The KaplanMeier method will be used to analyse
time to event (progression, mortality). Incidence and severity
of the (serious) AEs as per system organ class will be descriptively analysed.
No interim analysis is foreseen. A continuous safety
monitoring will be done by the DSMB in a blinded fashion.
All efforts will be made to collect complete CRF information
according to the protocol. This refers to all randomized
patients, treated or not treated with study drug. No missing
values regarding survival status and intracranial bleeds are
expected. However, for functional outcome parameters of
surviving patients. missing values might occur. The lastobservation carried-forward method will be applied in the
sense that data from the last available visit or measurement
will substitute the missing data. In case of missing values due
to death, the worst score principal will be applied.

Data management
The study uses an e-CRF available by password without a
specific online software for collecting and imputing efficacy

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and safety data, with specific codes identifying the patients
enrolled in the study, and verifying activities from investigators and clinical monitors. Electronic case report data will be
stored in a clinical trial database. An automatic control system
indicates the presence of discrepancies between the entered
data and the protocol requirement. Any data for which the
e-CRF will serve as the source document will be identified and
documented by each site in that sites study file. The e-CRF
allows monitors and data managers to check by password all
the entered data for each centre participating in the trial. The
monitors can see the SAE reports for each patient, the subject
visit calendar, the date of the three-month follow-up visits, the
number of the centres, and the number of enrolled patients.
As regard the neuroimaging data, all plain CT scans,
baseline and follow-up, are registered on CD-ROM or DVD,
labelled with the patients codified data and saved on a centralized database. There is a centralized reading of CT scans by
a neuroradiologist, member of the DSMB. The neuroradiologist must fill a report and send it via email to all centres. The
investigators have to change radiological data registered in the
e-CRF if they are different from the centralized report.

Study organization and funding

The management of TESPI trial includes a National Coordinator Centre (NCC) based at the Unita di Trattamento Neurovascolare, Department of Neurological Sciences, Policlinico
Umberto I, of the Sapienza University of Rome. The NCC is
assisted by the CRO based at the Centre for Clinical Research
of the Sapienza University of Rome (CRISC Centro di
Ricerca per la Sperimentazione Clinica). The study is overseen
by an Executive Steering Committee comprised of experts in
the fields of stroke, neurology, and clinical trials. The NNC
communicates both directly and through the CRO with 25
nationwide centres so far involved in the trial. Other centres
will be activated. TESPI is a non-profit study and it was
approved and funded by Agenzia Italiana del Farmaco (Italian
Medicines Agency, for the Drug approval and vigilance), with
the protocol number FARM65KNKY. This trial is registered in
the EudraCT (European Union Drug Regulating Authorities
Clinical Trials) database with the number 2007-006177-88
and in the Stroke Trials Registry of the Washington University
Internet Stroke Center (22).

S. Lorenzano et al.

in the next few years. For all these reasons and as i.v. thrombolysis with alteplase remains at the moment the only proven
effective pharmacological reperfusion therapy in acute ischaemic stroke, this therapeutic option should not be a priori
categorically denied to the widest component of the stroke
population represented by elderly. The threshold of 80 years
for thrombolytic treatment is arbitrary. But the stroke physician, with experience on thrombolysis, who visits a very
elderly patient with acute ischaemic stroke needs to carefully
assess the potential risks and benefits for that patient and
definitive recommendations on this topic can come only by
RCTs.

Study organization
Principal Investigator and National Coordinator: Danilo Toni.
Steering Committee: Cesare Fieschi (Chairman); Danilo Toni,
Domenico Inzitari, Roberto Sterzi, Antonio Carolei
(Members).
Data Monitoring Safety Board (DSMB): Gianluigi Lenzi
(Chairman); Marco Fiorelli, Annarita Vestri (Members).
CRO: Roberto Verna, Moira Cordisco, Ugo Lancia (CRISC
Centro di Ricerca per la Sperimentazione Clinica (Centre for
Clinical Research), Sapienza University, Rome, Italy); CRO
Scientific Board and Technical Coordinator: Paolo Primiero;
Administrative and monitoring Practices: Antonella Noy di
Lannoy.
Statistician: Annarita Vestri.
Local Coordinators: Roma, Policlinico Umberto I-D. Toni;
Bari F. Federico; Roma, Ospedale S. Andrea M. Rasura;
Verona P. Bovi; Milano, Ospedale S. Raffaele G. Comi; Pisa
G. Orlandi; Roma, Policlinico Gemelli V. Di Lazzaro;
Brescia M. Magoni; Roma, Policlinico Tor Vergata P. Stanzione; Modena M. Cavazzuti; Genova C. Gandolfo; Ferrara
M.R. Tola; Imperia M. Furlan; Firenze, Santa Maria
Annunziata M. Bruscoli; Perugia G. Agnelli; Roma,
Ospedale San Camillo C. Pozzessere; Firenze, Careggi
P. Nencini; Prato A. Vinattieri; Udine M. Valente; Vicenza
F. Perini; Pietra Ligure T. Tassinari; LAquila A. Carolei;
Cremona L. Bettoni; Cuneo P. Gerbino Promis; Torino
F. Melis.

References
Summary
TESPI has been designed to provide still lacking data on the
efficacy and safety of i.v. thrombolysis with rt-PA specifically
in patients aged over 80 years treated within three hours of
stroke onset, a field of clinical uncertainty in stroke medicine
and an issue with relevant social impact, great implications in
clinical practice and generally in healthcare organization that
needs to be urgently addressed. The incidence of stroke
increases exponentially with age, life expectancy has increased
over the past few decades, and it is expected to further increase

256

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