PRESS RELEASE ATTACHEMENT
released on 10 Sept. 2001
The
NAVIGATOR Study
Frequently
Asked Questions & Answers
Q.
Why has Novartis organized the NAVIGATOR study?
A. In the industrialised world, approximately 1 in
7 people aged over 40 years have a condition known as impaired glucose
tolerance (IGT). People
with IGT are at high risk of developing type 2 diabetes, a chronic
condition associated with severe health risks, including blindness,
kidney damage, and cardiovascular disease (CVD).
People with IGT are also at increased risk of CVD; indeed, many
people who develop type 2 diabetes already have cardiovascular
complications by the time they are diagnosed.
It is therefore important that we investigate measures to reduce
the risk of diabetes and CVD in the high-risk IGT group.
The NAVIGATOR study will
evaluate whether the oral antidiabetic nateglinide (Starlix®) or the
antihypertensive angiotensin II receptor blocker valsartan (Diovan®)
are effective at reducing progression to type 2 diabetes and CV
morbidity and mortality in people with IGT.
At present, there are no licensed treatments for IGT.
The NAVIGATOR study will be
the largest diabetes prevention trial ever conducted.
Q.
What outcomes will be measured in the NAVIGATOR study?
A. The NAVIGATOR study will
evaluate:
·
whether Starlix prevents or delays progression to
type 2 diabetes in people with IGT
·
whether Diovan prevents or delays progression to
type 2 diabetes in people with IGT
·
whether Starlix prevents or delays the development
of CVD in people with IGT
·
whether Diovan prevents or delays the development
of CVD in people with IGT
Q. How will
diabetes be diagnosed in the NAVIGATOR trial?
A. Type 2 diabetes will be
diagnosed if an individual’s fasting plasma glucose is 7.0 mmol/l (126
mg/dl) or greater and/or their plasma glucose level two hours after
consuming 75g glucose is 11.1 mmol/l (200 mg/dl) or greater. These
are the criteria for diagnosis of diabetes recommended by the World
Health Organisation.
Q.
What are the recruitment criteria for NAVIGATOR?
A. To be eligible for the NAVIGATOR study,
individuals must have IGT and be at least 50 years old with at least one
cardiovascular disease (e.g.
previous heart attack, angina) or at least 55 years old with at least
one cardiovascular risk factor (e.g.
family history of type 2 diabetes or premature heart disease, smoking,
hypertension).
Q. What is impaired
glucose tolerance (IGT)?
A. IGT is an intermediate
state between normal blood glucose control and type 2 diabetes.
In people with IGT, the rise in blood glucose that
occurs after consuming 75g glucose is greater than normal (although not
as great as in people with type 2 diabetes). Fasting blood glucose
levels are normal or moderately raised.
Q. How is IGT
diagnosed?
A. IGT is diagnosed from
measurements of fasting blood glucose (measured first thing in the
morning) and blood glucose two hours after consuming 75g glucose.
The latter test is known as an oral glucose tolerance test (OGTT).
Blood glucose measurements are
usually expressed as the level of glucose in plasma i.e.
the liquid phase of the blood that is left after the blood cells have
been removed.
IGT is diagnosed if:
·
plasma glucose two hours after consuming 75g
glucose is at least 7.8 mmol/l (140mg/dl) but below 11.1 mmol/l (200
mg/dl) i.e. between
‘normal’ and ‘diabetic’ levels.
·
fasting plasma glucose level is less than 7.0 mmol/l
(126 mg/dl) i.e. it may be
moderately raised, but it is below the threshold for diagnosis of
diabetes
Q. How common is
IGT?
A. Like type 2
diabetes, IGT results from a combination of impaired secretion of
insulin (the main hormone regulating blood glucose) and reduced
sensitivity of the body’s cells to insulin (insulin resistance).
In particular, people
with IGT show a defect in early insulin secretion (the phase of insulin
secretion that occurs immediately after eating).
This is caused by malfunctioning of the ß-cells of the pancreas
(which produce insulin).
The precise cause of
insulin resistance is unclear, but it tends to occur in individuals who
have excess body fat, particularly abdominal (central) fat, and who are
physically inactive. Studies
also suggest a link between insulin sensitivity and vascular function.
Q. Why was Starlix selected for the NAVIGATOR
study?
A. Starlix is an oral antidiabetic drug that, when
taken just before meals, prevents excessive rise in blood glucose by
stimulating early insulin secretion.
IGT (and type 2 diabetes) are characterised by loss of early
insulin secretion and raised post-meal blood glucose, so in theory,
Starlix is an ideal drug to use in the treatment of IGT.
It has been suggested that using Starlix to control
post-meal blood glucose in people with IGT will reduce the stress on the
pancreatic ß-cells that produce insulin. This might reduce the decline
in ß-cell function that ultimately leads to type 2 diabetes.
Q. Why was Diovan
selected for the NAVIGATOR study?
A. Diovan is an angiotensin II receptor blocker (ARB)
that reduces elevated blood pressure by causing dilation of blood
vessels. Drugs that block
the action of angiotensin II have been shown to reduce the incidence of
cardiovascular events in high-risk groups.
Evidence is also emerging that drugs that block the effects of
angiotensin II may reduce the risk of developing type 2 diabetes by
improving insulin sensitivity. The
NAVIGATOR trial will provide more information on how effective Diovan is
at delaying the onset of diabetes and preventing CV morbidity and
mortality.
Q.
Will the NAVIGATOR study assess the combined effect of Starlix and
Diovan?
A. The NAVIGATOR study will assess the effect of
Starlix and Diovan independently, not in combination.
Although some participants will receive both drugs, this
intervention has been included solely to reduce the number of
participants required. This is a standard design for clinical trials.
Q.
Will NAVIGATOR participants be allowed to take other therapies?
A. Participants in the
NAVIGATOR study may take other therapies, including aspirin,
lipid-lowering medications, and other antihypertensives.
However, patients taking another angiotensin II receptor blocker
(ARB), or another oral antidiabetic, will not be enrolled in the study.
Q.
How will adverse effects be monitored? Will participants who experience
adverse effects be removed from the trial?
A. Participants will be seen at two weeks, one
month, three months and six months into the study and every six months
thereafter. At every appointment, adverse effects will be assessed.
Serious side-effects are not expected, but if at any point, the
clinical investigator believes it is in the participant’s best
interest to withdraw from the trial, treatment will be discontinued.
Everyone who takes part in the trial for any length
of time will be followed up for type 2 diabetes and CVD. This will enable ‘intent-to-treat’ analyses to be
performed i.e. we will be able
to determine the probability of developing diabetes and CVD for
individuals who are given a particular drug, as well as for individuals
who take the drug over the whole period.
Q. What happens if
a study participant progresses to diabetes during the trial or has a
cardiovascular condition that worsens?
A. If a participant’s
condition worsens to diabetes or if it becomes necessary to treat a
worsening cardiovascular disease, other therapy will be discussed with
the participant and used with the participant’s consent.
Q.
Will the NAVIGATOR participants receive any lifestyle advice?
A.
Everyone taking part in the NAVIGATOR trial will receive lifestyle
advice, covering issues such as weight management and the importance of
physical activity, at all their appointments throughout the study.
The goals for weight loss and increased exercise will be similar
to the highly successful Finnish and US Diabetes Prevention Programs.
Q.
How long will the NAVIGATOR study last?
A. The NAVIGATOR study is
divided into two phases.
The first phase – evaluating the effect of
Starlix and Diovan (individually) on progression to type 2 diabetes –
will last for three years after the last patient is recruited.
This phase is expected to be completed in mid-2006. An interim
analysis of the effect on cardiovascular outcomes will also be conducted
at this time.
The second phase - evaluating
the effect of Starlix and Diovan (individually) on cardiovascular
outcomes - will last until 1,000 subjects have had a cardiovascular
event. It is expected that
this will take approximately five years nine months after the first
patient is recruited i.e. that
the second phase will be completed in mid-2007.
Q.
Where will the NAVIGATOR study be conducted?
A. NAVIGATOR is a
multi-centre, multinational trial.
It will be conducted in over 30 countries across the world, in
North America, South America, Europe, Asia, Australasia, and South
Africa. Approximately half the subjects will be recruited in Europe
and approximately a third in the United States.
Q.
How will subjects be recruited?
A. Subjects will be recruited using a number of
strategies, including referrals from physicians, advertisements, and
on-line recruitment.
Q.
How long will it take to enroll the 7,500 patients in NAVIGATOR?
A. It is expected to take
about 18 months to recruit all the study subjects, from November 2001 to
May 2003.
Q.
Who is the NAVIGATOR study’s lead investigator?
A.
There is not one lead investigator for NAVIGATOR but rather an Executive
Committee of lead investigators consisting of world-renowned
cardiovascular and diabetes experts from both the USA and Europe:
·
Rury Holman, Professor of Diabetic Medicine,
University of Oxford, UK
·
John McMurray, Professor of Medical Cardiology,
University of Glasgow, UK
·
Robert Califf, Associate Vice Chancellor for
Clinical Research, Duke Clinical Research Institute, Durham, USA
·
Steven M. Haffner, Professor of Medicine,
University of Texas Health Sciences Center, San Antonio, USA
Q. Why is the
NAVIGATOR trial only studying people over 50?
A. IGT tends to occur in middle age.
Selecting individuals over 50 years of age means that subjects in
the NAVIGATOR study are more likely to be ‘typical’ IGT patients.
Furthermore, as the risk of type 2 diabetes and CVD is much
greater in people over 50, selecting this age group will help to ensure
that a sufficient number of participants develop type 2 diabetes and CVD
over the duration of the trial to enable any effect of Starlix or Diovan
to be detected.
Q.
What are the current indications for Starlix and Diovan?
A. In the USA, Starlix is indicated both for use as
initial monotherapy (in drug naïve patients not chronically treated
with oral antidiabetics) and in combination with metformin, another oral
antidiabetic, in patients with type 2 diabetes whose blood glucose is
not controlled by diet and exercise.
In Europe, Starlix has been approved in combination
therapy with metformin in type 2 diabetes patients inadequately
controlled despite a maximally tolerated dose of metformin.
Diovan is licensed for the
treatment of hypertension (high blood pressure). Novartis has recently petitioned the FDA and other regulatory
bodies worldwide for an additional heart failure indication.
Diovan is also supported by the world’s largest clinical trial
programme for an ARB, which includes several studies besides NAVIGATOR
investigating its effects beyond blood pressure lowering.
Q.
How is NAVIGATOR different from the DREAM trial?
A. Both the NAVIGATOR and the
DREAM trials are evaluating the effects of an oral antidiabetic and an
antihypertensive on progression from IGT to type 2 diabetes.
However, they are investigating different agents with different
mechanisms of action and have different study designs and recruitment
criteria. Furthermore,
NAVIGATOR is a significantly larger trial than DREAM (7,500 subjects
compared to 4,000) and, unlike DREAM, is also investigating the effects
of antidiabetic/antihypertensive therapy on the development of CVD in
people with IGT.
Q.
How is NAVIGATOR different from the Diabetes Prevention Program?
A.
The Diabetes Prevention Program (DPP) evaluated the effect of the oral
antidiabetic metformin and intensive lifestyle advice on progression to
diabetes in people with IGT. NAVIGATOR will evaluate prevention
strategies other than those evaluated in the DPP. This will add further
to our data on diabetes prevention.
The
NAVIGATOR trial is a significantly larger trial than the DPP (7,500
subjects compared to approximately 3,000) and is taking place in about
40 countries rather than just in the USA. Also, unlike the DPP, the
NAVIGATOR trial will evaluate cardiovascular events as well as
progression to diabetes.
Q. How can I obtain
more information about NAVIGATOR?
A. For more information about
any aspect of the NAVIGATOR study, please e-mail your questions to wendy.morris@uk.ogilvypr.com
or call + 44 (0) 207 309 1116.
