Clinical Trial Details
— Status: Terminated
Administrative data
| NCT number |
NCT00456963 |
| Other study ID # |
09A502 |
| Secondary ID |
|
| Status |
Terminated |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
September 2007 |
| Est. completion date |
March 2010 |
Study information
| Verified date |
February 2024 |
| Source |
Istituto Auxologico Italiano |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Background. Antihypertensive therapy with ß-blockers (ßBs) and diureticts (Ds) is accompanied
by a higher incidence of diabetes mellitus (DM) than therapy with ACE-inhibitors (ACEIs) or
angiotensin-receptor blockers (ARBs). Whether this difference is due to an antidiabetogenic
action of ACEIs and ARBs or to the fact that these agents are free of the diabetogenic
activity of ßBs and Ds is unknown. Prevention of DM as well as of HT is of primary health
concern.
Objectives. The primary objective of PHIDIAS is to test whether in individuals with
components of metabolic syndrome making them predisposed to DM and HT, addition of either an
ACEI or an ARB to periodically reinforced lifestyle counselling can reduce 1) onset of DM and
2) onset of HT significantly more than lifestyle plus placebo. Secondary objectives are 1)
comparing the antidiabetogenic effects of ACEI and ARB, and 2) investigating whether the
effects of ACEI and ARB on DM and HT persist at least 6 months after treatment withdrawal.
Methods. PHIDIAS is a prospective, double-blind, placebo-controlled 3-arm comparison trial.
300 general practitioners (members of SIMG with the assistance of hospital centres of SIIA)
will randomise 6000 untreated individuals aged 40-75 years, with SBP 130-139 or DBP 85-89
mmHg, fasting glucose (FG) 100-125 mg/dl, waist circumference >= 102 (M) or >= 88 cm (W), to
three blinded treatments, given in addition to lifestyle advise: 1) Placebo; 2) the ACE
Enalapril (10 mg, then 20 mg od); 3) the ARB Losartan (50 mg, then 100 mg od).Double-blind
treatment will be maintained until 500 cases of DM are observed (presumably average of 36
months) (Treatment Phase: control visits, BP, FG every 6 months). This will be followed by a
6-month Withdrawal Phase (active treatment substituted by placebo). Primary outcomes are DM
(FG >= 126 mg/dl) and HT (SBP >= 140 or DBP >= 90 mmHg) on 2 consecutive visits. PHIDIAS will
be governed by a Steering Committee assisted by a blinded Event Adjudicating Committee and an
independent DMSB.
Expected results. The sample size is adequate (alfa 5%, power 90%) to evaluate whether
incident DM (expected rate 3.5%/year) or incident HT is reduced 25% by ACEI and ARB versus
placebo (primary hypothesis) and whether either the ACEI or the ARB reduces incident DM by
30% more than the other agent.
Description:
1. Background and rationale
1. Evidence available Data obtained from observational studies have shown that
subjects with hypertension have an increased prevalence of type II diabetes
mellitus compared to normotensives, and that the association between diabetes and
hypertension represents a markedly increased risk of cardiovascular disease (1).
Also the recent overview of the Blood Pressure Lowering Treatment Trialists'
Collaboration indicates that the risks for stroke, coronary events, heart failure,
and cardiovascular death are about twice as large in hypertensives with diabetes
than in hypertensives without diabetes, independently of absence of treatment or
use of different antihypertensive regimens (2). On the other hand, a number of
observational and randomised intervention trials has shown that antihypertensive
therapy may increase the risk of developing new diabetes mellitus in hypertensives
patients. This evidence has been reviewed and meta-analysed in several recent
papers (3,4). In brief, of 13 large randomised trials of antihypertensive therapy,
12 have shown a greater incidence of new diabetes mellitus in the treatment arms
using thiazide diuretics or beta-blockers (and often the two types of agent in
association) than in the treatment arms based on angiotensin converting enzyme
inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) or calcium antagonists
(CAs) (often with addition of thiazides and sometimes of beta-blockers) (3).
Furthermore, a recent review analysed 48 groups of subjects without diabetes
mellitus at the time of randomization in 22 clinical trials. 17 of such trials
enrolled patients with hypertension, 3 enrolled high risk patients, and only 1
enrolled patients with heart failure. The primary outcome was represented by
incident diabetes mellitus. Overall, the antihypertensive classes that were found
to be associated with newly developed diabetes mellitus were, in increasing order,
ACEIs, ARBs, followed by CAs and placebo (4). It is debated whether thiazide
diuretics and beta-blockers are really diabetogenic, by exaggerating or
accelerating the time-dependent tendency to develop diabetes, and whether ACEIs and
ARBs are antidiabetogenic by retarding this normal trend, or simply lack the
diabetogenic effect of thiazides/beta-blockers. The issue, of obvious clinical
importance, can only be solved by placebo-controlled studies, but
placebo-controlled studies are ethically difficult to be conducted nowadays when
evidence favouring active treatment of hypertension and cardiovascular risk is
overwhelming.
Nonetheless, data from a small number of placebo-controlled studies are available.
The diuretic chlorthalidone, often associated with a beta-blocker, has been
compared with placebo in elderly patients with isolated systolic hypertension in
the Systolic Hypertension in the Elderly Program (SHEP) trial: when the current
definition of diabetes was used (fasting glucose, FG, >=126 mg/dl), a significant
higher incidence of diabetes was found in the actively treated group (13 vs 8.7%,
p<0.0001) (5), a finding which substantiates the hypothesis that diuretic and
beta-blocker therapy exaggerates the trend towards developing diabetes, i.e. has a
diabetogenic effect. Placebo-controlled studies are also available concerning the
effects of ACEIs and ARBs on diabetes onset. Unfortunately, in all these trials
placebo groups were contaminated by administration of multiple therapies required
for the control of the cardiovascular pathologies of the patients under study. In
the Study on Cognition and Prognosis in the Elderly (SCOPE), concerning elderly
patients with hypertension, the use of hydrochlothiazide and beta-blockers was more
extensive in the so called "placebo" arm than in the active (candesartan) treatment
arm, and may explain the higher incidence of diabetes in the placebo than the
candesartan group (6). Likewise, in four large trials in which an ACEI or ARB were
compared to placebo in patients at high cardiovascular risk because of coronary
heart disease or heart failure, both the ACEI or the ARB and the placebo were given
on top of multiple background therapies required by the severity of the diseases
being investigated. Furthermore, little information is available from publications
of these trials as to what extent background therapies were modified during the
trials and whether these changes were balanced between the placebo and active
treatment arms of the trials (see 3). Therefore the issue whether ACEIs and ARBs
have an active antidiabetogenic action or simply lack the diabetogenic action of
thiazides and beta-blockers remains undecided, and any claim that agents blocking
the renin-angiotensin system exert an antidiabetogenic action appears unjustified.
Prevention of the onset of diabetes, as well as of hypertension, and even more of
the ominous association of diabetes and hypertension, remains, however, of primary
public health concern, because of the morbidity burden represented by these
ailments and the health care cost involved. Prevention must obviously be exerted
before a disease develops, and is most effective in those subjects in whom the risk
of developing the disease is high. Conditions predisposing to both hypertension and
diabetes are well known. Individuals with so-called high-normal blood pressure
(i.e., systolic blood pressure, SBP, 130-139,or diastolic blood pressure, DBP,
85-89 mmHg) have a 40% chance of becoming hypertensives (i.e.,SBP>=140 or DBP>=90
mmHg) over 4 years according to the Framingham Heart Study (7)and the initial
findings of the Trial Of Preventing Hypertension (TROPHY, 8). High-normal BP
together with impaired glucose tolerance (as indicated by fasting glucose, FG,
>=100 mg/dl), abdominal obesity, a low HDL-cholesterol and high triglycerides are
often found clustered in a large portion of populations both in USA and Europe, the
cluster being commonly referred to as the metabolic syndrome (MS) (9).
Independently of the current debate whether all manifestations of MS are due to a
common pathophysiological mechanism (i.e., insulin resistance), it is undisputed
that coexistence of high-normal BP, a raised FG and an elevated BMI is a very
strong predictor of both hypertension and diabetes mellitus.
2. Knowledge effect Lifestyle changes (suitable diet and physical exercise) are known
to be effective in preventing both hypertension (10) and diabetes (10-12), but
whether addition of an ACEI or ARB may further reduce both conditions is unknown.
Individuals with MS are ideal subjects for investigating whether agents blocking
the renin-angiotensin system exert a real antidiabetogenic effect in addition to
what can be achieved by non-pharmacologic measures, as there are no compelling
medical indications for treating these subjects with other drugs that may confound
interpretation of the findings. Therefore the PHIDIAS trial plans to study a large
cohort of individuals with high-normal BP, high FG (but below cut-off values of
diabetes) and abdominal obesity, all instructed to lifestyle changes. They will be
randomly and double-blindly assigned to placebo, or an ACEI or an ARB over a period
of approximately 3 years, in order to investigate whether blockade of the
renin-angiotensin system on top of lifestyle advise can further reduce onset of
diabetes, a hypothesis so far based only on animal studies suggesting that some
ARBs may be partial agonists of peroxisome proliferator-activated receptor gamma
(PPAR-gamma) involved in regulating insulin sensitivity (13). Furthermore, the
subject will be followed up for additional 6 months after withdrawal of randomised
medications to investigate whether the preventive actions are enduring and survive
medication.
3. Implication for AIFA and the NHS Both the conduct and the results of PHIDIAS are
expected to have favourable implications both for the Italian Agency for Medicinal
Products (AIFA) and the Italian National Health System (NHS). The conduct of a
trial such as PHIDIAS that is committed to general practitioners and involve
individuals at high risk of cardiovascular disease, will effectively promote
education to healthier lifestyle measures and help prevention of cardiovascular
disease and diabetes. The results of the trial will also have considerable impact
both on AIFA and the NHS: 1) if addition of an ACEI or ARB to lifestyle measures is
shown not to have any further preventive effect on diabetes, the claim of an
antidiabetogenic action of these agents will be disproved, and their use in
diabetes prevention discouraged; 2) if both an ACEI and an ARB are found to prevent
hypertension and/or diabetes, but their effects are not significantly different or
an ACEI is found more effective than an ARB, the use of a generic ACEI- such as the
one to be administered in PHIDIAS- will represent a benefit for the subjects
combined with considerable savings for the NHS; 3) if an ARB is found to be
significantly more effective than an ACEI in preventing diabetes, this will
implicate temporarily increased costs for the NHS, largely compensated on the long
term by the decreased or delayed onset of diabetes and hypertension, as well as
their complications.
4. Differences from other current trials PHIDIAS substantially differs from a few
ongoing trials of diabetes prevention. The Diabetes Reduction Assessment with
Ramipril and Rosiglitazone Medication (DREAM) trial (14-15) and the Nateglinide and
Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial (16)
are only directed to diabetes prevention. Both of them intend to test an ACEI
(DREAM) or an ARB (NAVIGATOR) versus an antidiabetic agent (rosiglitazone in DREAM,
nateglinide in NAVIGATOR ) versus placebo with a factorial design, in individuals
selected primarily on the basis of impaired glucose tolerance, so that other
cardiovascular conditions are not excluded: in DREAM 43% of recruited subjects are
hypertensives and 35% are dyslipidemic, and in NAVIGATOR previous cardiovascular
disease or risk factors are criteria for eligibility. Therefore in both studies the
investigation of the possible antidiabetogenic effect of the ACEI or ARB is likely
to be confounded to some extent by concomitant therapies for hypertension and
cardiovascular disease. Finally the TROPHY trial (8) is only planned for prevention
of hypertension (by the ARB candesartan) and is not exploring the equally important
issue of diabetes prevention by blockade of the renin-angiotensin system.
2. Objectives of the study
1. Primary objectives. In a group of individuals with high-normal blood pressure (SBP
130-139, or DBP 85-89 mmHg), FG in the high but nondiabetic range (100-125 mg/dl),
and abdominal obesity (abdominal circumference >= 102 cm in men and >= 88 cm in
women), i.e. with those characteristics of the so called MS that are major
predictors of DM and HT, the trial will explore whether addition of an agent
blocking the renin-angiotensin system (either an ACEI or an ARB) over periodically
reinforced instructions for suitable lifestyle changes reduces: 1) onset of
diabetes (defined as FG >= 126 mg/dl or need for antidiabetic therapy) or 2) onset
of hypertension (defined as SBP >= 140 or DBP >= 90 mmHg, or need for
antihypertensive therapy) to a significantly greater extent than addition of a
placebo.
2. Secondary objectives. In the same group of individuals, the trial will also
investigate whether 1) the diabetes preventing effects of an ACEI and ARB
significantly differ, because of the different blocking mechanisms on the
renin-angiotensin system, and the additional action on bradykinin and,
respectively, on PPAR gamma of the two agents, 2) the effects of the ACEI and ARB
on the onset of diabetes and hypertension are enduring, persisting 3 to 6 months
after substitution of the active drugs with placebo. Obviously, preventive effects
substantially surviving medication would strengthen the therapeutic role of these
agents, whereas disappearance of the effects after a short period would suggest a
masking effect only.
3. Study design
1. Study population
1. Inclusion criteria:
. Men or women of any racial background
- Age >= 40 years and <= 75 years
- SBP>= 130 mmHg and < 140 mmHg or DBP >= 85 mmHg and < 90 mmHg, average of
screening and randomisation visits (in absence of any antihypertensive
medication)
- FG >=100 mg/dl (5.6 mmol/l) and < 126 mg/dl (7.0 mmol/l) between
screening and randomisation (in absence of any antidiabetic medication)
- Waist circumference >= 102 cm in men and >= 88 cm in women.
2. Exclusion criteria (see below).
2. Enrolment procedures. The study subjects will be enrolled by general practitioners
associated with the Italian Society of General Practitioners (SIMG). Candidates for
enrolment will be identified by the participating physicians among subjects in
their NHS list attending their clinics. Each physician will be asked to enrol and
randomise 21 subjects within 1 year.
3. Trial design.
- Type of the study. This is a prospective, Italian, multicentre, double-blind,
randomised, placebo-controlled, 3-arm, parallel group comparison with a
response dependent on fixed-dose interventions.
- Interventions. At the randomisation visit, as well as at follow-up visits, at
6-month intervals, all subjects will receive written detailed instruction for
an adequate diet and physical exercise, with the goal of a body weight
reduction of at least 5% (see Annex 1).
In addition to lifestyle advise, all subjects will be randomised to one of the
three following blinded treatments:
1. Placebo : 1 Enalapril placebo tablet and 1 Losartan placebo tablet, once
daily.
2. ACEI : 1 Enalapril tablet and 1 Losartan placebo tablet, once daily.
3. ARB : 1 Losartan tablet and 1 Enalapril placebo tablet, once daily. During the
first four weeks, 10 mg Enalapril tablets and 50 mg Losartan tablets will be
used, and 20 mg Enalapril and 100 mg Losartan tablets will be used for the
rest of the treatment phase of the study. At the end of this phase, all
subjects will receive the two placebo tablets daily for six months (withdrawal
phase).
Among the ACEIs enalapril has been chosen as it has been the most widely prescribed
ACEI for about 20 years, is presently available as a generic agent, and is one of
the ACEIs for which a lower incidence of diabetes has been shown (SOLVD trial
[17]).
Among ARBs losartan may be chosen as animal studies indicates it may be a partial
antagonist of PPAR-gamma to a greater extent than other ARBs (18).
The detailed flow-chart of the study is in Annex 2.
4. Subject allocation. At the time of random allocation to double blind treatment an
individual number will be allocated to each individual subject and noted in the
clinical record form (CRF). The individual number determines which of the three
treatment schemes the individual will receive throughout the treatment period of
the study. By a computer-generated randomisation list prepared by the randomisation
centre using appropriate blocks each subject will be assigned to one of the three
treatment groups with identical probability. The individual numbers given to each
participating physician will be assigned to an individual subject in ascending
order.
5. Outcomes - Primary outcomes. Time to first event of:
1) New diabetes, defined as occurrence of a FG>= 126 mg/dl at any six-month visit
during the treatment phase, to be confirmed at a subsequent visit within one month;
or initiation of any antidiabetic treatment during the treatment period of the
trial.
2) New hypertension, defined as occurrence of a SBP>= 140 mmHg or of a DBP>= 90
mmHg at any six-month visit during the treatment phase, to be confirmed at a
subsequent visit within one month; or initiation of any antihypertensive treatment
during the treatment period of the trial.
- Secondary outcomes. Time to first event (during the treatment phase) of:
1. New diabetes (as defined above) or new hypertension (as defined above), which
comes first.
2. Major cardiovascular events (myocardial infarction, stroke, cardiovascular
death, heart failure, new documented angina, revascularization procedures )
plus death by non-cardiovascular causes.
3. Variations of SBP and DBP during the treatment phase and, separately, during
the withdrawal phase.
4. Variations fasting blood glucose during the treatment phase and, separately,
during the withdrawal phase.
5. Estimated creatinine clearance (Cockroft and Gault formula) lower than 60
ml/min in subjects with values >= 60 ml/min at baseline.
6. Serious adverse effects.
Incidence at the end of the final 6-month withdrawal phase of:
1) New diabetes (as defined above). 2) New hypertension (as defined above)[in order
to test the possibility of a "masking" effect of treatment].
3) Variations of SBP and DBP. 4) Variations of fasting blood glucose.
6. Information retrieval.
- Forms. All relevant information will be filled up in CRFs for the screening
and randomisation visits and all subsequent visits. When required additional
documentation will be attached to the related clinical form.
- Physical examination. See Annex 3.
7. Blood pressure measurement. See Annex 4.
8. Clinical laboratory measurements. See Annex 5.
9. Clinical Outcomes. See Annex 6.
l. Checking of bias and confounding. Compliance to randomised treatment will be checked
at each visit by counting return capsules, but even noncompliant individuals, as well as
individuals withdrawn from medication, will be kept in the trial. Careful search will be
made at each visit of concomitant medication used intermittently or continuously.
m. Follow up. As illustrated in Fig. 1 (Annex 2), follow-up visits will occur every 6
months (± 1). The trial (see Sample size calculation) will be event-driven, but it is
expected that the treatment phase will be of approximately 3 years.
n. Subjects lost to follow up The subjects being all in the NHS list of the
participating physicians, it is expected that loss to follow up will be minimal
(probably less than 5%), and will consist only of those subjects withdrawing their
consent to participate in the study (and not only to take randomised medication).
o. Monitoring of the study Monitoring of the entire study, committees, centres, and
participating practitioners will be the responsibility of the coordinating institution,
under the supervision of the Principal investigator. Monitoring of participating units
will be done electronically on a continuous way, with the support of a professional
agency.
p. Sample size estimates The primary hypothesis is that incidence of diabetes and,
separately, hypertension will be reduced by active treatment (cumulative data of
enalapril and losartan-treated groups) by 25% with respect to placebo treatment. For
evaluating this difference between the placebo group and the two actively treated groups
together, a two-tailed type I error of 5% and a power of 90% will be accepted. The main
secondary hypothesis is that either of the two active treatments (enalapril versus
losartan) will reduce incidence of diabetes by 25-30% more than the other, with a
two-tailed type I error of 5% and a power of 70-90%. On the basis of the Framingham
Heart Study data in high-normal BP subjects (7) and on initial findings of TROPHY (8),
incidence of hypertension in our study population can be expected to be close to 10% per
year. Assessment of the expected incidence of diabetes is more difficult because of
variable data provided by previous studies. In the hypertension trials that have
suggested a possible antidiabetogenic action of ACEIs and ARBs, annual incidence of
diabetes was between 1.2 and 4% (3), but those trials that have also explored predictors
of new diabetes suggest higher annual incidences in subjects at higher risk of diabetes,
as follows: 2.6% in ELSA, patients with metabolic syndrome (19), 2.7% in CAPPP, upper
risk tertile (20), 3.4% in LIFE, upper risk quartile (21), and 2.7% and 7.2% in VALUE,
third and fourth risk quartile (22) 6.2% in DREAM (15). Three recent trials
investigating interventions to prevent diabetes in subjects with impaired glucose
tolerance (presumably rather similar to those in PHIDIAS, as a multivariable definition
of risk such has ours has been shown to outperform a glucose tolerance test in
predicting onset of diabetes report yearly incidences of diabetes of 7.5% (23), 11% (23)
and 12.7% (24), reduced to 3.7-4.8% by intense lifestyle counselling. Finally, the DREAM
study (15) is based on the hypothesis that patients with impaired glucose tolerance have
a diabetes annual accrue rate of 4.5%. On the basis of this evidence, we have chosen a
conservative hypothesis of an yearly accrue rate of diabetes of 3.5%, i.e. an incidence
of 10.5% in 3 years. This being a lower incidence rate than that expected for
hypertension, the sample size has been calculated on the diabetes rate. It has been
assumed that, supposing a 4.8% loss to follow-up, a placebo-treated group of 2000
subjects will develop 200 cases of diabetes in three years, and the two actively treated
groups, of 2000 subjects each, will develop altogether 300 cases of diabetes. These
numbers will provide the required alpha of 5% and power of 90% to detect 25% reduction
of diabetes incidence in the two active treatment groups together (7.5% in 3 years)
compared to the placebo group (10% in 3 years). As to the secondary hypothesis, 2000
subjects in each of the enalapril or losartan groups will be sufficient to detect a
lower incidence of 25% in one group (6.4% incidence in 3 years) versus the other (8.5%)
(alpha 5%, power 72%) or a lower incidence of 30% (6.2 versus 8.8 in 3 years) (alpha 5%,
power 88%), again supposing a 4.8% loss to follow-up. In any case the study will be
event driven, and continued until 500 cases of diabetes are observed.
q. Organisation PHIDIAS will be governed by a Steering Committee, chaired by the
Principal Investigator (A.Zanchetti) and formed by 7 other members (G. Mancia, B.
Trimarco, M. Volpe, E. Agabiti Rosei, C.Cricelli, A. Filippi, G. Corrao). A Data
Monitoring and Safety Committee, chaired by L. Berrino and formed by G. Corrao, and E.
Ambrosioni, will monitor the study and review two interim analyses (180 and 360
accumulated cases of diabetes) using previously agreed conservative warning rules for
efficacy and harm. An Operating Committee (A. ZAnchetti, M. Valentini, F. Gregorini, A.
Filippi, E. Romagnoli)will supervise the daily management of the trial. An Endpoint
Committee will provide an independent and blinded assessment of efficacy endpoints (G.
Mancia, M. Volpe). Participating Units will be general medicine physicians associated
with SIMG. The Italian Society of Hypertension (SIIA) in accordance with SIMG will
identify a number of hospital hypertension centres located in areas close to the
participating units, able to provide consulting assistance to the participating
physicians, and yearly sessions of lifestyle counselling for the enrolled subjects. A
Monitoring Unit will be established at the coordinating institution, liaising with a
professional agency (Yghea, Bologna, Italy). A Statistical Unit will also be located at
the coordinating institution under the supervision of G. Corrao, with the responsibility
of randomising treatments, collecting data and analysing them at trial end. No
centralized laboratory is considered nor structured lifestyle support, nor oral glucose
tolerance tests for diagnosis of diabetes, as the trial intends to reproduce, as far as
possible, the conditions under which the NHS can operate.
r. Feasibility The Principal Investigator, Alberto Zanchetti, has a long and extensive
experience in running trials of antihypertensive treatment and treatment of
atherosclerosis (see curriculum vitae). As Scientific Director of the Coordinating
Institution, he confirms that Istituto Auxologico Italiano, IRCCS, accepts to conduct
the study and agrees for the use of the human and technological resources described in
the study protocol.
s. Timing The trial is expected to start about 6 months after eventual AIFA approval.
Recruitment of subjects is expected to be completed in one year. The treatment phase,
although its duration is event-driven, is expected to last an average of 3 years,
followed by a controlled withdrawal phase of 6 months. Predefined check points for
recruitment are at 6, 9, 12 months from study start. Interim analyses from the DMSC are
also considered (see above). A final report is expected within 1 year from study end.
t. Statistical analyses Data analysis will proceed according to CONSORT guidelines for
randomised controlled trials and to the intention-to-treat principle. Analysis are
detailed in Annex 7. In brief, there will be summary statistics on baseline variables,
while primary and secondary efficacy variables will be analysed as time to onset of
diabetes or hypertension, using a Cox regression model adjusted for selected number of
variables.
u. Ethical aspects. The trial is not expected to have potential risks for study
subjects. They have clinical characteristics for which no drug treatment is currently
indicated, and all of them will benefit by receiving detailed healthy lifestyle
counselling. The subjects will receive full written information on the study, and sign
an informed consent document. Approval has been obtained from the Ethical Review
Committee of the Coordinating Institution and will be obtained from those of the NHS
units from which the participating physicians depend.
4. Annex
1. Annex 1. Lifestyle Interventions. At the randomising visit, all subjects will
receive written detailed instructions for adequate diet and physical exercise, with
the goal of a body weight reduction of at least 5%, as follows: diet: total fat
intake of less than 5% of energy consumed, saturated fat to less than 10% of energy
consumed, frequent intake of vegetables, fruit, olive oil (see ref. 8); exercise:
moderate exercise, such as walking, jogging, swimming for 30 min at least 5 days a
week Instructions will be reiterated at each 6-month visit, when adherence to
lifestyle measures and their results will be checked and annotated in the clinical
form. Recruited subjects will also be offered the possibility of an annual teaching
session on healthy lifestyle provided by a hospital hypertension centre located in
the vicinity
2. Annex 2. Study Flow-Chart
Notes:
1.The randomised treatment phase may be prolonged or shortened (and the withdrawal phase
delayed or anticipated) according to the accrual time for the primary outcome diabetes (500
cases) 2.Each time a BP or diabetes outcome is measured, an additional confirmatory visit
should be scheduled within one month 3.In individual cases, additional visits may be
scheduled at the physician's discretion 4.The randomised treatment doses are fixed for all
subjects. However in individual cases, the physician may decide to withdraw medication
(possibly temporarily, followed by rechallenge) but the subject should be maintained in the
trial to preserve intention to treatment.
c. Annex 3. Physical examination. For all physical examinations attention should be focused
on cardiovascular signs and symptoms. The initial physical examination (screening visit) and
the final one comprise the examination of the head, thorax, abdomen, spinal column,
auscultation of the heart and lungs, inspection of the skin, and measurement of bodyweight
and body height, and measurement of waist circumference. To measure waist circumference,
locate top of right iliac crest and place a measuring tape in a horizontal plane around the
abdomen at the level of the iliac crest. Measure at the end of a normal expiration. At
follow-up visits, physical examination comprises a short check of all organ systems including
auscultation of the heart and lungs, and a check for signs and symptoms of cardiovascular
diseases. Waist circumference and body weight must be measured at all follow-up visits. Data
will be recorded in specific boxes on Clinical Report Forms
d. Annex 4. Blood pressure measurement. Using a calibrated standard sphygmomanometer or a
validated digital device and appropriate size cuff, blood pressure will be measured with the
subjects' arm supported at heart level. Systolic and diastolic blood pressure will be
recorded by the investigator at phase I and V of Korotkoff sounds, or as indicated by the
digital device. The cuff should be deflated at a rate not greater than 2 mmHg/sec with the
patient sitting quietly for several minutes. Blood pressure will be measured 3 times at 1 min
intervals. Blood pressure will be measured in all subjects at the screening and randomization
visits, and during all follow-up visits at 6-month intervals. If a value of SBP>= 140 or
DBP>=90 mmHg (cut-offs for hypertension) is measured at a follow-up visit, this should be
confirmed during a second visit within one month. If the participating physician decides for
antihypertensive treatment, the use of a calcium antagonist is less likely to interfere in
either way with development of diabetes.
e. Annex 5. Clinical laboratory. Haematology: haemoglobin, haematocrit, red blood cell count,
white blood cell count, platelet count will be measured before randomization and study end.
Biochemistry: fasting glucose will be measured before randomization and at all follow-up
visits at 6-month intervals Fasting triglycerides, total cholesterol, HDL- cholesterol,
creatinine, potassium, AST (SGOT), ALT (SGPT), as well as proteinuria (dip stick) will be
measured before randomization and subsequently at yearly intervals.
f. Annex 6. Clinical outcomes. Death and the cause of death will be documented in the
clinical report form of the first visit missed by a deceased individual. Non fatal
cardiovascular and renal events will be documented by careful inquiry with the subject and
family members, and every effort will be made to obtain hospital or similar documentation
when available.
g. Annex 7.Statistical analysis. Data analysis will be performed according to CONSORT
guidelines for randomised controlled trials and to the intention-to-treat principle.
1. Comparability between groups Summary statistics on demographic and clinical baseline
variables will be calculated by treatment group, and comparisons between treatment
groups will be performed. Analysis of variance models or nonparametric tests will be
utilized for continuous variables, whereas Mantel-Haenszel, Cochran-Mantel-Haenszel,
chi-square or Fisher's exact tests will be performed for between-group comparison of
categorical variables, as indicated.
2. Analysis of primary efficacy variables The time-to-event primary efficacy variables
(time to onset of diabetes and time to onset of hypertension, during the treatment phase
of the trial) will be analysed separately for diabetes and hypertension, using a Cox
regression model including treatment (placebo vs treatment), and the following baseline
covariates: age, gender, race, BMI, FG, SBP, DBP. Subgroup analyses will be performed
based at least on the following criteria: age groups, gender, BMI and FG groups (above
and below medians), SBP and DBP (above and below medians). The assumption of
proportional hazards will be checked for using graphic methods, and a secondary analysis
of sensitivity will be performed utilizing the log-rank test.
3. Analyses of secondary efficacy variables Secondary variables for which time-to-event can
be defined will be analysed using the same models as for the primary variable. For the
secondary efficacy variables for which time-to-event cannot properly be calculated
(incidence of diabetes and hypertension at the end of the final 6-month withdrawal
phase), logistic regression models will be utilized adjusting for factors as for primary
variable analysis.
