The second INTEnsive blood pressure Reduction in Acute Cerebral haemorrhage Trial. An international randomised controlled trial to establish the effects of early intensive blood pressure lowering in patients with intracerebral haemorrhage.

SUMMARY PROTOCOL

THE SECOND INTENSIVE BLOOD PRESSURE REDUCTION IN ACUTE CEREBRAL HAEMORRHAGE
TRIAL
The main phase of an academic lead and conducted, international, multi-centre,
open label, blinded endpoint,
randomised controlled trial to establish the balance of benefits and risks of a
treatment strategy of early
intensive lowering of blood pressure (BP) compared to a conservative BP
lowering policy in patients with
acute primary intracerebral haemorrhage (ICH) and co-existing elevated BP
without any definite indication
or contraindication to treatment.

Intracerebral haemorrhage (ICH) is one of the most serious subtypes of stroke,
affecting over a million
people worldwide each year, most of whom live in Asia. About one third of
people with ICH die early after
onset and the majority of survivors are left with major long-term disability.
Despite the magnitude of the
disease burden and cost on healthcare resources, there remains uncertainty
about the role of surgery for
ICH and no acute medical therapies have been shown to definitely alter outcome
in ICH. Although
administration of activated recombinant human Factor VII (ie rFVIIa;
NovoSeven®) has been shown to limit
haematoma expansion, a recent clinical trial failed to show that this effect
translated into improved survival
and less major disability in ICH. Moreover, future use of this agent will be
limited by its short therapeutic time
window, contraindication in patients at risk of thromboembolism, and high cost.
The management of ICH,
therefore, contrasts sharply with that of acute ischaemic stroke, where there
is now strong evidence to
support the routine use of thrombolysis in carefully selected patients, and
aspirin in the majority.
Blood pressure (BP) levels are strongly and positively associated with the
incidence of first and recurrent
stroke, and there is definitive evidence that BP lowering reduces stroke risk.
Although BP levels are
commonly elevated early after the onset of stroke, particularly in ICH, the
effects of BP lowering treatment in
the acute phase of stroke remain unknown. As a consequence, there are wide
ranging guideline
recommendations for the management of elevated BP in the setting of acute ICH.
While these provide an
indication of perceived harm associated with *very high* BP levels (>220mmHg),
they also highlight persisting
clinical uncertainty about what comprises optimal management of BP in this
patient group.
The adverse effect of high BP levels on outcome in ICH is likely to involve a
number of different
mechanisms: elevated hydrostatic pressure at the site of bleed is likely to
result in a larger initial bleed and
early haematoma expansion, while elevated BP increases the likelihood of early
re-bleeding, more severe
oedema and early recurrent stroke. The first of these mechanisms is likely to
be most relevant in the first
several hours after onset, as haematoma expansion is most frequent in the first
several hours after onset.
Reduction of BP may also be important sub-acutely, as peri-haematomal oedema,
which appears to be
plasma derived, increases in volume over several days. Against this background
of processes is the
increased risk of early stroke recurrence from elevated BP levels.
The INTERACT2 study follows the recently completed initial pilot study
(vanguard phase) which established
the feasibility of the protocol, safety of early intensive BP lowering, and
effects on haematoma expansion
within 6 hours of onset of ICH. Having established *proof-of-concept* that BP
lowering may improve outcome
by reducing haematoma expansion, INTERACT2 aims to establish the effects of the
treatment on major
clinical endpoints in patients with ICH recruited from an expanding clinical
network around the world.

To establish the effects of a management policy of early intensive BP lowering
on death and disability in
patients with acute spontaneous, primary, ICH and co-existing elevated BP
compared to a more
conservative BP management policy that is based on a commonly used guideline
for the management of
high BP in this clinical setting. The study uses a similar design to the pilot
study - INTERACT1 - undertaken
in 44 sites in Australia, China and South Korea during 2005-2007. All patients
will contribute to assessment
of the mortality/dependency endpoint at 90 days follow-up post-randomisation.

A multi-centre, prospective, open label, blinded outcome, randomised,
controlled, trial involving 2800 patients
with acute ICH recruited from approximately 140 sites in the world.

Patients will be randomised via a 24-hour central internet-based randomisation
system (or IVRS system,
currently in development) to either (a) intensive or (b) conservative
management of BP. Treatment is to start
as soon as possible after randomisation (eg in the emergency department) and
will be continued in a
monitored facility (ie intensive care unit, high dependency unit, or stroke
unit) for all randomised patients.
Intensive BP lowering - patients allocated to the intensive BP lowering group
will be started on a
standardised treatment regime commencing with intravenous and then changed when
feasible to oral (or via
a nasogastric tube) agent(s). The treatment goal is to achieve a systolic BP
goal (<140 mmHg) within one
hour of commencing the randomised treatment. The second goal will be to
maintain the systolic BP to 140
mmHg or less or at least 7 days in hospital, and subsequently on discharge and
for 90 days postrandomisation.
Specific treatment protocols are developed for each participating region/centre
based on the
availability of BP lowering agents for routine use.
Conservative BP lowering - patients allocated to this group will receive BP
management that is based on
American Heart Association (AHA) guidelines. In this group, the threshold to be
considered for the initiation
of treatment will be a systolic BP -180 mmHg.
For both groups, patients must be on an oral anti-hypertensive agent by day 7
or discharge from acute care
hospital, with a long-term target systolic BP of 140 mmHg, as per secondary
stroke prevention guidelines.

Data collection and follow-up:
Key baseline information will be collected at the time of randomisation.
Follow-up data will be collected on four occasions: 24 hours and 7 days (or at
the time of death or hospital discharge, if this should occur before day 7),
and 28 days and 90 days, with the latter two assessments able to be carried out
either in-person or over the telephone.
Most of the baseline and follow up assessments are part of the routine
procedures for any patient admitted with an intracerebral haemorrhage.
The following examinations will be performed specifically for study puposes:
On day 1: NIHSS (standard on admission, but not standard at day 1);
On day 7: NIHSS, modfied Rankin Scale;
On day 28: modified Rankin Scale, Euroquol 5D.
On day 90: modified Rankin Scale, Euroquol 5D.
The duration of the contact at day 28 and 90 will be around 30 minutes.

Risks:
The blood pressure lowering drugs may cause side effects. These are generally
mild and infrequent, and may be resolved immediately by reducing or stopping
the treatment, but can include hypotension (low blood pressure), dizziness,
headache, vomiting and other drug-specific side effects.
A theoretical severe and irreversible side effect is ischaemic stroke due to
the rapid lowering of blood pressure and circulation in the brain.
As with any medication, an allergic reaction to blood pressure lowering drugs
is possible, but is quite rare.
In INTERACT 1, the pilot study including 404 patients with an intracerebral
haemorhage and high blood pressure, early, intensive treatment of high blood
pressure was feasible and safe (Lancet Neurology, mei 2008).
The CT-scan <24 hours (+/- 3 hours) after randomisation entails a very small
additional exposure to radiation.