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Final version 7.12 2 June 2004
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Risk factor Identification and Assessment in Hypertension and Diabetes
(RIAHD) study.
A survey and assessment of cardiovascular risk factors in Swedish hypertensive and
diabetic patients.
Study Chair:
RIAHD study organization,
Thomas Hedner, Department of Clinical Pharmacology,
Sahlgrenska University Hospital, Göteborg, Sweden.
Supported by:
The Swedish Society of Hypertension
Lennart Hansson Memorial Fund
Sponsor:
Bristol-Myers Squibb
Sanofi-Synthelabo
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TABLE OF CONTENTS
SUMMARY ................................................................................................................................... 4
1. STUDY OBJECTIVES ............................................................................................................. 5
Primary Objective ................................................................................................................... 5
Secondary Objectives .............................................................................................................. 5
Background ................................................................................................................................. 5
Hypertension ........................................................................................................................... 5
Diabetes .................................................................................................................................. 6
Hyperviscosity ......................................................................................................................... 8
Inflammartory and endothelial markers ................................................................................. 8
Clinical Judgement ................................................................................................................ 7
Microalbuminuria/ albuminuria ............................................................................................. 6
Type 2 diabetes and renal protection...................................................................................... 7
Diabetes, hypertension and microalbuminuria - population in Sweden................................. 8
MARELD ................................................................................................................................. 8
3. STUDY DESIGN ..................................................................................................................... 10
4. SELECTION AND ENROLLMENT OF SUBJECTS ........................................................ 11
Selection of centres in RIAHD ............................................................................................. 11
Exclusion criteria .................................................................................................................. 11
Inclusion criteria High risk group (Hypertension, DM and MA/A) ..................................... 11
Inclusion criteria Low risk group (Hypertension but no DM or MA/A) .............................. 12
Study Enrollment Procedures ............................................................................................... 12
5. CLINICAL AND LABORATORY EVALUATIONS ......................................................... 12
Risk assessment .................................................................................................................... 12
Blood sampling ..................................................................................................................... 13
Clinical Judgement................................................................................................................ 13
Health Care consumption ...................................................................................................... 13
Home Blood Pressure ........................................................................................................... 13
Schedule of Evaluations ........................................................................................................ 14
Special Instructions and Definitions of Evaluations ............................................................. 14
6. SUBJECT SAFETY ................................................................................................................ 17
7. STATISTICAL CONSIDERATIONS .................................................................................. 17
Parameters ............................................................................................................................. 17
Sample size ........................................................................................................................... 18
Statistical methods ................................................................................................................ 18
Interim analysis ..................................................................................................................... 19
8. STUDY DURATION .............................................................................................................. 19
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9. STUDY ORGANIZATION .................................................................................................... 19
10. ETHICAL AND REGULATORY STANDARDS ............................................................. 19
11. STUDY CONDUCT .............................................................................................................. 20
Responsibilities of the Clinic(s) ............................................................................................ 20
Responsibilities of the Organizers/Sponsors ........................................................................ 20
Source document requirements ............................................................................................. 20
The use and completion of case report forms (CRFs) .......................................................... 21
12. ADMINISTRATIVE POINTS AND PROCEDURES ...................................................... 21
Record retention in investigating centre(s) ........................................................................... 21
13. CONFIDENTIALITY
14. OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS................................. 22
15. CLINICAL STUDY REPORT ............................................................................................ 22
16. PUBLICATIONS .................................................................................................................. 22
17. PROTOCOL AMENDMENTS ........................................................................................... 22
18. BIBLIOGRAPHY ................................................................................................................. 23
GLOSSARY AND ABBREVIATIONS ……………………………………………………
22
APPENDICES ............................................................................................................................. 26
Study Organisation And Participating Clinical Sites ............................................................ 27
Key study individuals (names and address) ..............................................................................
Study sites (Investigators and study nurses) .............................................................................
Study Flow ................................................................................................................................
Study organization ....................................................................................................................
RIAHD Screening (the RIAHD High Risk Group) ..................................................................
RIAHD Screening (the RIAHD Low Risk Group) ...................................................................
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SUMMARY
Study Title
Risk factor Identification and Assessment in Hypertension and Diabetes (RIAHD) study. A
survey and assessment of cardiovascular risk factors in Swedish hypertensive and diabetic
patients
Objectives
The primary objective of the RIAHD study is:
- Assessment of novel circulating cardiovascular risk factors (RF) such as blood viscosity
and inflammatory markers in high-risk patients, i.e. those with hypertension, diabetes and
micro/ macroalbuminuria versus age and gender matched low risk patients, i.e. those with
hypertension without diabetes or micro/ macroalbuminuria.
Secondary objectives of the RIAHD study include:
- To assess objective cardiovascular risk in high and low risk patients according to
European Society of Hypertension/European Society of Cardiology (ESH/ESC)
Systematic Coronary Risk Evaluation system (SCORE)
- Assessment of subjective expressed risk (clinical judgment) by physicians and patients
- Assessment of Home Blood Pressures and Office Blood Pressures to establish
cardiovascular risk in cohorts
- Assessment of the potential impact of selected genetic polymorphisms of cardiovascular
relevance on risk profile in terms of other risk factors, associated clinical conditions
(ACC) and presence of target organ damage (TOD)
- Assessment of health economic impact of disease by evaluating health care utilisation,
and sick leave
- Reassessment of cardiovascular and metabolic morbidity as well as total mortality after 5
years
Design and Outcomes
RIAHD is a multicentre cardiovascular screening of RF, ACC and TOD in high-risk patients
(hypertension, diabetes and micro/ macroalbuminuria), in comparison with low risk patients
(hypertension without diabetes or micro/ macroalbuminuria)
Visits and Duration
The study will include one clinic visit where risk factors will be assessed by medical history,
medical examination, blood sampling, blood pressure (BP) assessments and questionnaires.
The study informed consent will also include the possibility of a five-year follow-up.
Sample Size and Population
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By screening of representative cohorts of patients/subjects, 500 high-risk patients (hypertension,
diabetes and micro/ macroalbuminuria) and 500 low-risk patients (hypertension without diabetes
or micro/ macroalbuminuria) will be included in the protocol.
1. STUDY OBJECTIVES
Primary Objective
The primary objective of the RIAHD study is:
- Assessment of novel circulating cardiovascular risk factors (RF) such as blood viscosity
and inflammatory markers in high-risk patients, i.e. those with hypertension, diabetes and
micro/ macroalbuminuria versus age and gender matched low risk patients, i.e. those with
hypertension without diabetes or micro/ macroalbuminuria.
Secondary Objectives
Secondary objectives of the RIAHD study include:
- To assess objective cardiovascular risk in high and low risk patients according to
European Society of Hypertension/European Society of Cardiology (ESH/ESC)
Systematic Coronary Risk Evaluation system (SCORE)
- Assessment of subjective expressed risk (clinical judgment) by physicians and patients
- Assessment of Home Blood Pressures and Office Blood Pressures to establish
cardiovascular risk in cohorts
- Assessment of the potential impact of selected genetic polymorphisms of cardiovascular
relevance on risk profile in terms of other risk factors, associated clinical conditions
(ACC) and presence of target organ damage (TOD).
- Assessment of health economic impact of disease by evaluating health care utilisation
and sick leave
- Reassessment of cardiovascular and metabolic morbidity as well as total mortality after 5
years
Background
During the next decade cardiovascular metabolic disease will rank as the number one cause of
morbidity and mortality in the world. Especially, hypertension and diabetes will increase in the
developing world and this will account for a dramatic increase in complications (Murray and
Lopez, (A and B) 1997). Due to this evolving scenario, novel strategies are needed to improve
detection, treatment and follow up. In particular, preventive measures have to be implemented in
order to influence the global increase in cardiovascular and cerebrovascular disease.
Hypertension
Hypertension is a major risk factor for stroke and myocardial infarction (ESH/ESC Guidelines
2003). There is an increasing prevalence of systolic hypertension in the elderly, a condition,
which seems to be carrying even more risk than diastolic hypertension. Also there is an increase
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in patients with masked hypertension i.e. those patients who have high blood pressure on
ambulatory or home blood pressure readings compared to clinic readings.
In particular, hypertension patients with additional risk factors (RF) as well as those with
associated clinical conditions (ACC) and target organ damage (TOD) are at particular risk. In
such patients, blood pressure levels for initiating treatments and also target levels on treatment
are lower than those in low risk patients.
Diabetes
In Sweden approximately 400000 patients have diabetes mellitus, 15% type-1 (IDDM) and 85%
type-2 (NIDDM). Of the NIDDM patients, approximately 35% have accompanying
hypertension. Furthermore approximately 30% of all hypertensive patients with NIDDM have
microalbuminuria.
Patients with hypertension, diabetes, and renal disease are at very high risk for developing
cardiovascular (CV) disease. Because there is the potential to delay the progression of renal
disease and reduce the risk of CV disease in this high-risk hypertensive population, it is
important to identify patients with risk factors for NIDDM, renal disease, and CV disease and
target them for early, aggressive anti-hypertensive therapy. (The sixth report of the JNC 1997,
WHO Hypertension guidelines 1999)
The pool of at-risk hypertensive patients include:
 All patients with diabetes mellitus
 All patients with microalbuminuria and proteinuria
 All hypertensive patients with CV or renal disease or with multiple risk factors for CV or
renal disease
Microalbuminuria/ albuminuria
Normally functioning kidneys preserve virtually all of the protein in the circulation. Therefore,
the presence of abnormal levels of protein in urine (proteinuria) is a sign of kidney damage or
malfunction. Albumin represents a portion of the circulating protein and is a reliable measure of
the amount of daily protein excretion in the urine. The normal daily urinary excretion of albumin
is less than 30 mg/day. The urinary albumin excretion rate (UAER) of individuals who have
microalbuminuria is between 30 mg/day and 300 mg/day. When the UAER is greater than 300
mg/day, the condition is called proteinuria. (The terms macroalbuminuria and proteinuria are
often used interchangeably.)
One of the major risk factors for development of microalbuminuria is hypertension (Bakris
1996). Microalbuminuria is thus very important, since it identifies hypertensive patients at high
risk for renal and CV disease that could benefit from early intervention. Prospective studies have
shown that patients with type-2 DM and microalbuminuria have nearly 2½ times greater risk for
death from any cause and 2 times the risk of CV events and death (Dinneen, 1997). But, even if
it is easy to test for, and is a very reliable indicator of the earliest stage of renal disease,
screening for microalbuminuria is often overlooked in at-risk patients.
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NIDDM and renal protection
The IRMA 2 trial (Parving et al, 2001) was a double blind, placebo-controlled study conducted
in 590 patients with hypertension, type 2 diabetes and microalbuminuria (early stage kidney
disease).
The angiotensin II receptor antagonist (AIIRA) irbesartan, 300 mg taken once daily,
demonstrated a 70 percent relative risk reduction (p<0.001) in the progression from an early to a
later and more serious stage of kidney disease (also called diabetic nephropathy) compared with
patients who did not receive irbesartan, despite achievement of comparable levels of blood
pressure reduction in all groups. Based on IRMA 2 findings, for every 10 hypertensive patients
with type 2 diabetes and microalbuminuria treated with irbesartan 300 mg daily for 2 years, it is
anticipated that one patient would avoid developing more advanced diabetic renal disease within
the two years.
The IDNT trial (Lewis et al 2001) was a double blind, placebo-controlled study conducted in
1,715 patients with hypertension, type 2 diabetes and proteinuria (late stage kidney disease).
Irbesartan demonstrated a 20 percent relative risk reduction (p=0.02) in the primary endpoint
(progression to the first occurrence of: doubling of serum creatinine, end-stage renal disease or
all-cause mortality) versus the control group (placebo in addition to other antihypertensive
therapies). Irbesartan further demonstrated a 23 percent relative risk reduction (p=0.006) in the
primary endpoint versus the antihypertensive drug amlodipine, a calcium channel blocker.
Irbesartan yielded these protective effects in addition to achieving blood pressure reduction
similar to that observed in the comparator groups.
Although there was not a statistically significant difference among the treatment groups in the
overall secondary composite endpoint of fatal and nonfatal cardiovascular events, patients in the
irbesartan group had a 37 percent reduction of hospitalisations due to congestive heart failure
compared to those receiving the antihypertensive amlodipine (p<0.001) and a 23 percent
reduction (p=0.15) when compared to patients in the control group.
The RENAAL (Brenner et al 2001) trial was designed in a simmilar way as IDNT. It was a
double-blind, placebo-controlled study conducted in 1513 patients with type 2 diabetes and
proteinuria. Losartan was superior to the control group (placebo in addition to other
antihypertensive therapies) and demonstrated a 16 percent relative risk reduction (ARR 3,6%,
p=0.02) in the primary endpoint (progression to the first occurrence of: doubling of serum
creatinine, end-stage renal disease or all-cause mortality. Patients in the losartan group also
demonstrated a 32 percent reduction of hospitalizations due to congestive heart failure compared
to those receiving placebo including the antihypertensive amlodipine (p<0.005).
American Diabetes Association has published a revised position statement on diabetic
nephropathy (ADA recommendations 2001), incorporating recent evidence from those studies.
Diabetes has become the most common cause of end-stage renal disease (ESRD) in the US and
Europe. Over half of the diabetic patients starting on dialysis have type-2 diabetes and the
estimated costs for this are expected to grow enormously in the near future. The referred studies
above have demonstrated that the onset and course of diabetic nephropathy can be ameliorated,
but interventions have their greatest impact if instituted at a point very early in the course of the
disease.
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ADA recommends an annual screening for microalbuminuria since a high proportion of patients
with type-2 diabetes are found to have microalbuminuria or overt nephropathy shortly after the
diagnosis of their diabetes. The finding of microalbuminuria is an indication for screening for
possible vascular disease and for aggressive intervention to reduce all cardiovascular risk factors.
To reduce the risk and/or slow the progression of nephropathy, blood pressure control should be
optimised. The primary goal of anti-hypertensive therapy among diabetic patients is to decrease
blood pressure to <130 mmHg systolic and <80 mm Hg diastolic since hypertension markedly
accelerates the progression of diabetic nephropathy. Among patients with type-1 diabetic
nephropathy, ACE inhibitors are the initial agents of choice. Among hypertensive patients with
type-2 diabetes and microalbuminuria or clinical albuminuria, AIIRAs are the initial agents of
choice. These recommendations are based on the positive results of IRMA 2, IDNT and
RENAAL, and they represent the first time that AIIRAs are officially recommended as initial
drugs of choice for any indication.
Diabetes, hypertension and microalbuminuria - population in Sweden
Table 1 shows the frequency of patients with DM, type-2 DM and the percentage with
hypertension and microalbuminuria. This is an estimate of the population in Sweden from which
the RIAHD high-risk study cohort will be selected.
Table 1
DM
type-2
HT
U-albumin > 30mg/day
%
100
85
35
40
n patients
400000
340000
119000
47600
MARELD
MARELD (Micro Albuminuria and Risk Evaluation in Diabetes) is a quality assurance registry
to initiate routines for measurements and evaluations of the local frequency of microalbuminuria
in the diabetic population in Sweden. Over 12.000 but less than 13 000 patients with diabetes are
screened for microalbuminuria. If the test is positive, a new test is performed after 3 months. If
the test is still positive, the patient fulfils the criteria for microalbuminuria (Socialstyrelsen
1998). Risk factors are noted in a protocol, and in the case of hypertension, anti-hypertensive
drug used is noted. The forms are then collected for evaluation. In this screening approximately
20% of the diabetic patients will fulfil the criteria for cardiovascular high-risk patient as stated in
the follow up RIAHD protocol.
Hyperviscosity
Epidemiological and clinical studies have demonstrated a link between classical risk factors and
hemorheological markers such as fibrinogen as well as whole blood and plasma viscosity.
Changes have been shown in patients with renal disease, ischaemic heart disease, or peripheral
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arterial disease in addition to hypertension (De Backer et al, 2002). Viscosity is a parameter that
traditionally has been used to describe the rheological properties of a fluid. Viscosity is a
relationship between “shear stress” and “shear ratio” which is a measure of flow resistance in
blood towards the formation. The viscosity of blood is determined by a number of “structural”
factors such as hematocrit, plasma viscosity, erythrocyte aggregation and erythrocyte
deformability (Jonsson et al, 2002). Whole blood viscosity is influenced by a number of factors.
It tends to increase with age and also there is an influence by the lipid profile since viscosity
correlates positively to increased LDL as well as VLDL cholesterol and negatively to HDL
cholesterol. Hypertension is also linked to an increased whole blood viscosity and there is also an
increase in viscosity in smokers. Changes in the whole blood viscosity have also been linked to a
worse cardiovascular prognosis (Jonsson et al, 2002).
Today, blood viscosity is not used in risk categorization of patients with increased risk for
cardiovascular complications. Furthermore there are no intervention studies since blood viscosity
has not previously been a target for treatment. Therefore, blood viscosity is still a risk factor that
needs to be investigated further in order to illustrate its potential in cardiovascular risk
syndromes.
Inflammatory and endothelial markers
Several markers of inflammation are elevated in patients with cardiovascular risk syndromes.
Studies that have evaluated the relevance of high sensitive CRP (Hs-CRP, typically 1-3 mg/l), in
contrast to the levels used in clinical practice (>10mg/l), have been shown to predict CV
morbidity in associated clinical conditions. (Kuller et al., 1996, Ridker et al., 1997) Hs-CRP is
thought to represent a low-grade inflammation in the arterial vessels wall in association with
atherosclerosis (Ross 1999).
Clinical judgment
Evidence-based medicine (EBM) integrates clinical experience and patient values with the best
available research information. There are four steps in incorporating the best available research
evidence in medical decision making: asking answerable questions; accessing the best
information; appraising the information for validity and relevance; and applying the information
to patient care. Applying EBM to individual patients requires drawing up a balance sheet of
benefits and harms based on research and individual patient data.
Over the past few years, researchers have looked at the causes of practice variation between
physicians using essentially non-Brunswikian methods. The RIADH study will center on the
investigation and management of cardiovascular disease in general and in metabolically
compromised patients in particular. These diseases, diabetes, microalbuminuria and
hypertension, their investigation and management are all associated with high morbidity and
cost, and are the subject of high levels of public and health service concern. In RIAHD, we will
study the causes of medical practice variation in this area and examine some reasons why
physicians make treatment choices that do not appear to be based on the best available evidence.
Many initiatives have taken to improve medical treatment decisions. Educational strategies for
doctors have been effective in at least 50% of cases. Some reflection on one's own performance
seems to be a common feature of the most effective strategies. So far, such reflections have
mainly focused on the observed outcomes of the doctors' decisions, i.e. on what doctors do in
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practice. In order to assess what doctors really do, and not only what they express what they do,
analysis of judgment process itself may be useful (Kirwan et al 1990).
Health economics
Economics is becoming increasingly important in health care, since budget constraints are
becoming tougher. Increased spending in health care is due to an ageing population,
technological advances and changing disease epidemiology, among other factors. The focus on
economics means that the introduction of a new intervention or test should be evaluated from an
economic as well as from a medical point of view. A health economic analysis will be performed
as a part of RIAHD, which will cover direct as well as indirect costs for patients in each group.
The aim is to evaluate whether there are differences in health care consumption and productivity
loss between the two groups. Data collection will be from patients and their physicians by a
questionnaire.
Questions will be asked on the normal daily occupation, on the patients' perception on how their
health status influences their possibility to perform their daily tasks and on absenteeism during
the last four weeks prior to filling out the questionnaire. Median wage, obtained from SCB
(Statistics Sweden), will be used as a proxy for valuing the indirect cost.
Data on health care utilization, including visits to general practitioners, hospital visits, inpatient
periods, and consumption of pharmaceuticals will be collected for the 12-month period prior to
filling out the questionnaire. Costs for resources used will be taken from national DRG data,
from county council price lists, form the official price list for pharmaceuticals, and from other
sources.
3. Study Design
For visual overview of the study design and organization, see Appendix.
This study is a survey of the cardiovascular risk factors in patients with of a combination of
hypertension, diabetes mellitus and microalbuminuria in middle-aged to elderly patients in
Sweden.
The expected number of patients/subjects to be recruited is 1 000. The participants will be
recruited from outpatient units in Sweden. By screening of representative cohorts of
patients/subjects, 500 high-risk patients (hypertension, diabetes and micro/ macroalbuminuria)
and 500 low risk patients (hypertension without diabetes or micro/ macroalbuminuria) will be
included in the protocol. High-risk patients from the MARELD registry could be included
directly in the RIAHD study after verifying inclusion requirements for the high-risk group, i.e.
presence of hypertension, diabetes mellitus and micro/ macroalbuminuria (Appendix).
All patients will be tested for microalbuminuria and diabetes. A form will completed for medical
history, cardiovascular RF, ACC and TOD as well as any current medical treatment.
Blood pressure will be measured in the clinic as well as at home (self measurement).
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Questionnaires will be finalized for risk assessment by the patient as well as the physician.
Blood sampling will be performed for indirect (calculated) blood viscosity by using total protein
and hematocrit as well as by using fibrinogen and other inflammatory parameters. In a subgroup
of patients, blood viscosity will be assessed by using direct viscosity measurements with the
Bohlin Rheometer.
Blood, serum and plasma will also be sampled and analysed for inflammatory and endothelial
markers as well as selected genetic polymorphisms.
Additional markers, reflecting low-grade inflammation or endothelial damage, that are being
assessed are as follows; inflammatory (TNFa, IL1a, IL1b, IL2, IL4, IL6, IL8, IL10, NCP1, EGF,
VEGF and IFNg) and endothelial (ICAM, VCAM, vWF), by the Randox Biochip array
(www.randox.com). In addition BNP is measured as a global marker for cardiovascular risk.
Blood will also be stored in a biobank for analysis of genetic polymorphisms related to the 5year-follow-up of cardiovascular and metabolic morbidity and mortality as well as total
mortality. No other use of the biobank will be allowed outside cardiovascular and metabolic
morbidity and mortality as well as total mortality
4. SELECTION AND ENROLLMENT OF PATIENTS
Selection of centres in RIAHD
Study cohort patient selection will be based on the investigator network generated for the
MARELD registry that will be able to include sufficient number of patients, e.g. 10 high-risk and
10 matched low-risk patients/ centre. Furthermore, RIAHD patient recruitment will also take into
account the geographical distribution in Sweden.
Reference cohort patient selection will be based on a cohort of non-diabetic patients who are
negative in screening for microalbuminuria/albuminuria (MA/A) but on treatment for
hypertension based on a history of increased systolic and/or diastolic blood pressures (140/90
mmHg).
Exclusion criteria
- Any condition that prevents the patient giving their informed consent such as dementia,
aphasia etc
- Inability to perform Home Blood pressure measurements, laboratory tests, answering
study questionnaires or other study related procedures.
- Active drug or alcohol use or dependence that, in the opinion of the site investigator,
would interfere with adherence to study requirements.
- Serious illness that prevents the patient/subject participating in the study.
- Inability or unwillingness of subject or legal guardian/representative to give written
informed consent.
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Inclusion criteria High risk group (Hypertension, DM and MA/A)
-
Male and female age > 40 years
Treated systemic hypertension (systolic and or diastolic)
Diabetes mellitus type 2
Micro- or macroalbuminuria
Inclusion criteria Low risk group (Hypertension but no DM or MA/A)
- Male and female age > 40 years
- Treated systemic hypertension (systolic and or diastolic)
- Absence of diabetes mellitus
- Absence of micro- or macroalbuminuria
Study Enrolment Procedures
Screening
1.
2.
3.
4.
5.
Informed consent
Exclusion criteria
Clinic seated blood pressure measurement
Fasting blood/ plasma glucose
Microalbuminuria assessment with Micral or other MA/A test. If the test is positive or
if the patients have a diagnosed MA/A, a quantitative U-creatinine/ U-protein ratio
test is mandatory for the correct diagnosis of MA/A (see Appendix).
6. Inclusion criteria
If enrolled;
1. Physical examination
2. Registration of medication
3. Registration of risk factors (RF, ACC, TOD)
4. Blood sampling (viscosity, inflammatory and endothelial markers, genetics)
5. Physician questionnaire (Clinical jugement)
6. Home BP (self BP measurement)
7. Patient questionnaire (Clinical judgement and health care consumption)
5. CLINICAL AND LABORATORY EVALUATIONS
Risk assessment
Evaluation of risk factors, TOD and ACC will be performed according to the ESH/ ESC
guidelines (Appendix). Criteria for diagnoses for ACC will are given in Appendix.
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Blood sampling
Blood sampling will be made for evaluation of serum plasma and whole blood parameters
(Appendix 7), for routine laboratory evaluation (see section below) as well as for additional
evaluations of circulating inflammatory and endothelial markers (see below).
Clinical judgement
The objectives of the Clinical judgment part in RIAHD study is to analyze the processes
underlying the real and not only expressed clinical judgment process, give examples of its use in
the medical context, and discuss its potential for improving prescribing decisions. Clinical
judgments analysis can thus look behind the outcome of a decision to the underlying decision
process itself. Carefully constructed or selected real or written patient case histories as well as
constructed “paper patient” case material is required for this analysis. By using this technique of
real and “paper patient” cases, doctors' clinical judgment and prescribing behavior will be
assessed in the RIAHD study through the series of simulated (paper patients) case presentations.
Health care consumption
A health economic analysis will be performed, covering direct and indirect costs for patients in
each group. The purpose of this is to see if there is a difference in health care consumption and
productivity loss between the two groups.
Questions are asked on the normal daily occupation, on the patients' perception on how their
health status influences their possibility to perform their daily tasks and on absenteeism during
the last four weeks prior to filling out the questionnaire. Median wage, obtained from SCB
(Statistics Sweden), will be used as a proxy for valuing the indirect cost.
Data on health care utilisation, including visits to general practitioners, hospital visits, inpatient
periods, and consumption of pharmaceuticals will be collected for the 12-month period prior to
filling out the questionnaire. Costs for resources used will be taken from national DRG data,
from county council price lists, form the official price list for pharmaceuticals, and from other
sources.
Schedule of Evaluations
Evaluation
Screening
Informed Consent
X
Screening and matching
X
Enrolment
Physical Examination
X
Registration of medication
X
Registration of RF, ACC, TOD
X
Blood samples
X
Physician questionnaire (CJ)
X
1v
Postevaluation
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Home Blood Pressure
X
Patient Questionnaire (CJ and HCC)
X
Post-eval
X
Suitable patients will be screened after having been informed on and accepted the objectives of
the study, the procedures, the information which could be drawn from this survey, the potential
benefits for a better understanding of his disease.
The physician or the nurse will provide a full explanation of the procedure for urine screening to
the patient.
Fasting plasma or blood glucose measurement is performed.
The clinic blood pressure is measured after some minutes in the sitting position according to
standard procedures.
A urine sample is collected, preferably by overnight urine for testing of MA/A. The diagnosis of
MA/A for the high-risk patient group should be confirm by a quantitative U-creatinine/ Uproteinuria test.
The patient will be enrolled provided all inclusion and no exclusion criteria are present. Low-risk
patients should be matched versus high-risk patients (Appendix).
Additional examinations, laboratory tests and questionnaires
During the patient visit, or at home, questionnaires will be finalized by the patient as well as by
the physician for risk assessment.
Blood will be sampled for indirect (calculated) blood viscosity by haematocrit and total protein
as well as by other methods including fibrinogen in all patients.
In available patients close to Sahlgrenska University hospital, blood viscosity will also be
assessed by the Bohlin Rheometer. This will provide a methodological assessment of the indirect
(calculated) blood viscosity measurements.
Blood, serum and plasma will also be sampled for inflammatory and endothelial markers and for
measurement of serum/plasma markers as well as selected genetic polymorphisms. A biobank
will be created for analysis of genetic polymorphisms related to the 5-year-follow-up of
cardiovascular and metabolic morbidity and mortality as well as total mortality. No other use of
the biobank will be allowed outside cardiovascular and metabolic morbidity and mortality as
well as total mortality.
Special Instructions and Definition of Evaluations
Microalbuminuria
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Microalbuminuria will be assessed with reagent strips (Micral tests® Roche, see Appendix).
Physical examination
Wight, length and blood pressure measurements (BPM): BPM will be performed in the sitting
position according to ESH/ESC standard routines by sphygomanometry.
Registration of medication
Medical treatment is defined as any current Rx or OTC pharmaceuticals. See appendix (CRF).
Registration of risk factors
Medical history will be evaluated according to the questionnaire in appendix (CRF). The
questions are in accordance with the cardiovascular risk factor stratification as described in the
ESH/ESC Guidelines 2003. Cardiovascular and cerebrovascular disease will also be assessed for
the year preceding the screening visit.
Standard Laboratory Evaluations
S-Creatinine, EVF, S-protein, S-cholesterol, fS-LDL, HDL, fS-TG, fS-glucose, CRP, fibrinogen,
HbA1c, and other relevant screening tests will be performed and analysed by standardised
clinical chemistry methods.
Additional evaluations of circulating markers
Additional markers, reflecting low-grade inflammation or endothelial damage, to be assessed are
as follows; inflammatory (TNFa, IL1a, IL1b, IL2, IL4, IL6, IL8, IL10, NCP1, EGF, VEGF and
IFNg) and endothelial (ICAM, VCAM, vWF), by the Randox Biochip array (www.randox.com).
In addition BNP will be assessed as a global marker for cardiovascular risk.
Sampling for selected genetic polymorphisms and planned 5 year follow up
Analysis of selected cardiovascular and metabolic genetic polymorphisms related to the planned
5-year-follow-up of cardiovascular and metabolic morbidity and mortality as well as total
mortality.
Physician questionnaire
The examining physician will perform a regular clinical status assessment. Further on, a clinical
assessment by the physician of the individual cardiovascular risk of the patient will be
performed. Selected questions will be put to the physician to assess their expressed as well as
real judgements on cardiovascular and metabolic health risks in accordance with the
questionnaire described in appendix, CRF.
Patient questionnaires
The patient will perform a self-assessment of his/her own cardiovascular risk in accordance with
the questionnaire described in appendix (CRF).
Treatment history will be assessed for one year preceding the screening visit. All contacts with
health care providers will be listed. Selected questions will be put to patients to assess their
expressed as well as real judgements on cardiovascular and metabolic health risks.
Home (self) blood pressure measurement
Final version 7.12 2 June 2004
16
After appropriate training of the patient, home blood pressure will twice daily be assessed during
5 consecutive days. A semi-automatic device will be used. The blood pressure are measured both
in the morning, before leaving home if relevant, and in the afternoon after returning home. The
patient will rest for 5 minutes and the blood pressure should be measured in the sitting position.
At each occasion two measurements are registered in the patient book. (Appendix).
Definitions of history/ risk-factors
Hyperlipidemia
- Treated or detected hyperlipidemia (S-cholesterol >5mmol/l and/or LDL>3mmol/l, diet
or medical anti-hyperlipidemia treatment)
Overweight
- Abdominal circumference male>102, female >108
Smoking
- Former smoker
- Current smoker
CRP
- >1mg/ml
Stroke
- Rapidly occurring clinical signs of focal brain damage, obviously not caused by nonvascular mechanism. Symptoms regarded focal are: unilateral or bilateral motor
disturbance unilateral or bilateral sensory disturbance, aphasia/dysphasia, hemianopsia,
deviation conjugée, diplopia, dysphasia with rapid onset, apraxis with rapid onset, ataxia
with rapid onset, disturbance of perception with rapid onset.
- Global symptoms are accepted in a patient with subarachnoid haemorrhage or who is
deeply comatose excluding those caused by failing systemic circulation (shock, AdamsStrokes syndrome or hypertensive encephalopathy).
Ischemic heart disease
- Angina pectoris, myocardial infarction or previous percutaneous transluminal cardiac
angioplasty (PTCA) or cardiac angioplasty bypass graft (CABG)
Angina pectoris
- Symptomatic or treated angina pectoris: if PTCA or CABG has been performed and no
symptoms remain, a check in ischemic heart disease should be preferred.
Cardiac failure
- Clinical history of cardiac failure or UCG with ejection fraction (EF) <45%
Atrial fibrillation
- Diagnosed paroxysmal atrial fibrillation, atrial fibrillation on admission to the hospital or
during the observation period
Claudicatio intermittens
- Diagnosis of peripheral arterial disease or symptomatic claudicatio intermittens with
ankle brachial index <0,9
Carotid stenosis or surgery
- Known carotid stenosis of > 50% or history of carotid surgery
Retinopathies
- Diagnosed retinopathies
Renal diseases
Final version 7.12 2 June 2004
17
- Diabetic nephropathies
- Severe renal disease
- Albuminuria or elevated S-Creatinine
TOD
- LV-hypertrophy
- Carotid plaque
- Other cerebrovascular or cardiovascular disease
6. SUBJECT SAFETY
Monitoring
Since no drug will be administered in the frame of this protocol, no serious adverse event or
adverse events related to research procedures are expected. However, general medical safety
concerns should be exercised in case any unexpected safety issue should occur.
Safety instructions specific to the trial
In case any event would occur in the study, it will be recorded and reported (Appendix)
7. STATISTICAL CONSIDERATIONS
Parameters
The primary parameters studied in this study will be:
-
Levels of viscosity and inflammatory markers between groups and in relation to different
cardiovascular risks in hypertensive patients
Secondary parameters studied:
-
Score of cardiovascular risk factors in high-risk patients (hypertension, diabetes and micro/
macroalbuminuria) vs. low risk patients (hypertension without diabetes or micro/
macroalbuminuria).
-
Determination of blood glucose markers in relation to risk factors in patients with micro/
macroalbuminuria and hypertension.
-
Assessment of inflammatory and endothelial markers.
-
Assessment of “clinical judgment” in terms of physicians and patients risk assessment.
-
Assessment of Home Blood pressures and Office blood pressures to establish cardiovascular
risk in cohorts with established hypertension.Assessment of the potential impact of selected
genetic polymorphisms of cardiovascular relevance on risk profile in terms of other risk
Final version 7.12 2 June 2004
18
factors, associated clinical conditions (ACC) and presence of target organ damage
(TOD).Determine achieved clinic and home blood pressure levels and anti-hypertensive
treatment in this group of patients.
-
Assessment of health economic impact of disease by evaluating health care utilisation, sick
leave, direct pharmaceutical treatment cost.
-
Reassessment of cardiovascular and metabolic morbidity as well as total mortality after 5
years.
Sample size
In all, 500 high-risk patients (HT, DM and MA) and 500 low-risk patients (HT, no DM or MA)
will be included in the study.
The primary objective of the study is to measure and compare blood viscosity parameters in two
different patient populations. The power law coefficients, n and k, which are unique to each
blood sample, are related with blood viscosity parameters in the form of a mathematical
equation. Further on they are fixed independently of the shear rate. In a study (Hussain MA,
Puniyani RR 1999) the power law coefficient, n, was (0.703 ± 0.027) in patients with a
cardiovascular event (i.e. stroke) compared to n = (0.708 ± 0.025) in healthy controls. One goal
of the proposed study is to test the null hypothesis that the two population means are equal. The
criterion for significance (alpha) has been set at 0,050. The test is 2-tailed, which means that an
effect in either direction will be interpreted. With the proposed sample size of 500 and 500 for
the two groups, the study will have power of 85,9% to yield a statistically significant result.
This computation assumes that the mean difference is 0,005 (corresponding to means of 0,708
versus 0,703) and the common within-group standard deviation is 0,026 (based on SD estimates
of 0,025 and 0,027).
This effect was selected as the smallest effect that would be important to detect, in the sense that
any smaller effect would not be of clinical or substantive significance. It is also assumed that
this effect size is reasonable, in the sense that an effect of this magnitude could be anticipated in
this field of research.
On average, a study of this design would enable us to report the mean difference with a precision
(95,0% confidence level) of plus/minus 0,003 points. For example, an observed difference of
0,005 would be reported with a 95,0% confidence interval of 0,002 to 0,008. The precision
estimated here is the median precision. Precision will vary as a function of the observed standard
deviation (as well as sample size), and in any single study it will be narrower or wider than this
estimate.
Statistical methods
Population characteristics (including demographics, severity of the disease, co-morbidities,
current treatment or no treatment) will be summarized into count of non-missing data, mean,
Final version 7.12 2 June 2004
19
standard deviation, minimum, maximum, median, 5% percentile and 95% percentile for
quantitative variables and count and percentage of the population for categorical data. The
outcomes may be detailed by region.
Interim analysis
No interim analysis is planned in this study.
8. STUDY DURATION
The total duration of the study will be determined by the rate of recruitment and presence of
events in the study population. Estimated recruitment rate: Each centre will find approximately 2
high risk patients and 2 low risk patients (matched) every working week. The RIAHD study is
planned to start Q4 2004 and to be completed within 3-6 month.
9. STUDY ORGANIZATION
This is a multicenter study involving approximately 50 centres (general practioners) in Sweden
organized by a Steering committee. The study will be coordinated by the sponsor.
CRFs will be in paper form, transformed and sent by mail for data processing.
Centralized data and statistical analyses will be performed by a 3rd party statistical unit.
Centre set up
The sponsor will ensure centre set up and training of the centre staff.
Data Monitoring
During data entry, predefined compulsory data will be checked and supplementary information
will be asked for from the investigator. On site monitoring will not be performed.
10. ETHICAL AND REGULATORY STANDARDS
Ethical principles
This protocol is in accordance with the principles laid down by the 18th World Medical
Assembly (Helsinki 1964) and amendments laid down by the 29th WMA General Assembly,
Tokyo, Japan, October 1975, 35th WMA General Assembly, Venice, Italy, October 1983, 41st
WMA General Assembly, Hong Kong, September 1989, 48th WMA General Assembly,
Somerset West, Republic of South Africa, October 1996 and the 52nd WMA General Assembly,
Edinburgh, Scotland, October 2000.
Final version 7.12 2 June 2004
20
Laws and regulations
This protocol is also in accordance with laws and regulations in Sweden as well as relevant and
applicable guidelines.
Informed consent
It is the responsibility of the Clinic to obtain informed consent in compliance with national
requirements from each subject prior to entering the study or, where relevant, prior to evaluating
the subjects’ suitability for the study.
Ethics Review Committee
The Investigator will submit this protocol to the Ethics Review Committee. The Investigator is
required to forward a copy of the written approval/advice signed by the chairman to the sponsor.
On the approval/advice sheet, the trial (title, protocol number and version), the documents
studies (protocol, informed consent material), advertisement when applicable) and the date of the
review should be clearly stated.
11. STUDY CONDUCT
Responsibilities of the Clinic(s)
The Clinic(s) undertake(s) to perform the study in accordance with good clinical practice and
specifically either good clinical practice for study on medicinal products in the European
Community (ISBN-92 825 9563-3) or 21 CFR-part 312 subpart D and guidelines for the
monitoring of clinical investigations.
The Clinic is required to ensure compliance with respect to procedures required by the protocol.
The Clinic agrees to provide all information requested in the Case Report Form in an accurate
and legible manner according to instructions provided.
Responsibilities of the Organizers/Sponsors
The Sponsors of this study have responsibilities to Health Authorities to take all reasonable steps
to ensure the proper conduct of the study as regard to ethics, protocol adherence, integrity and
validity of the data recorded on the case report forms.
The Sahlgrenska Academy, Göteborgs University, takes the full responsibility to handle the
collected data and biobank according to current regulations and to devote necessary resources
and get necessary permissions for this.
The sponsor has the right, but no obligations, to take part of the 5-year follow up part of the
study. An inquiry should be sent to the sponsor before the planned 5-year follow up part is
executed.
Source document requirements
Patients’ hospital records will be source documents.
Final version 7.12 2 June 2004
21
The use and completion of case report forms (CRFs)
It is the responsibility of the Clinic to prepare and maintain adequate and accurate CRFs, which
have been designed by the Sponsors to record all observations and other data pertinent to the
clinical investigation. All CRFs should be completed in their entirety in a neat, legible manner to
ensure accurate interpretation of data; a black ballpoint pen should be used to ensure the clarity
of reproduced copies of all CRFs when faxed, sent by regular mail or collected on site. All
Clinics are encouraged to fill in the electronic CRF from (details to be provided by the
Sponsors).
Should a correction be made, the information to be modified must not be overwritten. The
corrected information will be transcribed next to the previous value with the reason for the
correction, initialled and dated by the authorized person.
12. ADMINISTRATIVE POINTS AND PROCEDURES
Curriculum vitae
An updated curriculum vitae will be obtained from all investigators.
Record retention in investigating centre(s)
The Clinic must maintain all study records, patient files and other source data for the maximum
period of time permitted by the hospital, institution or private practice.
However national regulations should be taken into account, the longest time having to be
considered.
For study performed in the European Community, the Clinic is required to arrange for the
retention of the patient identification codes for at least 15 years after the completion or
discontinuation of the study.
Any centre will notify the sponsor before destroying any data or records.
13. CONFIDENTIALITY
All materials, information (oral or written) and unpublished documentation provided to the
Investigators (or any company/institution acting on their behalf), inclusive of this protocol and
the patient Case Report Forms, are the exclusive property of the Sponsor and may not be given
or disclosed, either in part or in whole, by the Investigator or by any person under his/her
authority to any third party without the prior express consent of the Sponsor.
However, the submission of this protocol and other necessary documentation to the Ethics
Committee (IRB/IEC) is expressly permitted, the IRB/IEC members having the same obligation
of confidentiality.
Final version 7.12 2 June 2004
22
The Investigator shall consider all information, results, discoveries, records accumulated,
acquired, or deduced in the course of the study, other than that information to be disclosed by
law, as confidential and shall not disclose any such results, discoveries, records to any third party
without the Sponsor’s prior written consent.
14. OWNERSHIP OF DATA AND USE OF THE STUDY
RESULTS
The Sahlgrenska Academy, Göteborg University has the ownership of all data and results
collected during this study and acts under the supervision of the Steering committee. The
biobank is owned by the Sahlgrenska Academy, Göteborg University.
15. CLINICAL STUDY REPORT
A Clinical Study Report will be prepared based on the results of the study.
16. PUBLICATIONS
In multicentre study conducted by a Steering Committee, the responsibility for presentations
and/or publications is linked to the Steering Committee. The Steering Committee must send a
copy of the manuscript or abstract to the Sponsor for review at least forty-five (45) days before
submission.
All the study participants (Clinics and Committee members) will make a prior delegation of
responsibility for primary presentation and/or primary publication of the results to the Steering
Committee. No other publication is allowed before the primary publication. Any presentation or
publication by any one that participates in the study must mention the study and must be
approved by the Steering Committee in advance. Moreover, it is mandatory to make reference to
the primary publication.
17. PROTOCOL AMENDMENTS
It is specified that the appendices attached to this protocol and referred to in the main text of this
protocol form an integral part of the protocol.
No changes or amendments to this protocol may be made by the Clinic or by the Sponsor after
the protocol has been agreed to and signed by both parties unless such change(s) or
amendment(s) have been fully discussed and agreed upon by the Clinic and the Sponsor. Any
change agreed upon will be recorded in writing, the written amendment will be signed by the
Clinic and by the Sponsor and the signed amendment will be appended to this protocol.
Final version 7.12 2 June 2004
23
Approval/advice of amendments by Ethics Review Committee or similar body (IRB, CCPPRB)
is required prior to their implementation, unless there are overriding safety reasons.
If the change or deviation increases risk to the study population, or adversely affects the validity
of the clinical investigation or the subject’s rights, full approval/advice must be obtained prior to
implementation. For changes that do not involve increased risk or affect the validity of the
investigation or the subjects’ rights, approval/advice may be obtained by expedited review,
where applicable.
In some instances, an amendment may require a change to a consent form. The Clinic must
receive approval/advice of the revised consent form prior to implementation of the change. In
addition, changes to the Case Report Forms, if required, will be incorporated in the amendment.
Prior to initiating the changes, protocol amendment must be submitted to the Ethics committee(s)
involved.
18. BIBLIOGRAPHY
Murray CJ and Lopez AD. (A) Global mortality, disability, and the contribution of risk factors:
Global Burden of Disease Study. Lancet 1997; 349: 1436-42.
Murray CJ and Lopez AD. (B) Regional patterns of disability-free life expectancy and disabilityadjusted life expectancy: Global Burden of Disease Study. Lancet 1997; 349: 1347-52.
ESH/ESC Guidelines. J Hypertens. 2003; 21: 1011-1053.
Practice guidelines for primary care physicians: 2003 ESH/ ASC hypertension guidelines. J
Hypertens. 2003; 21: 1779-1788
The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure. Arch Intern Med. 1997; 157: 2413-2446.
Guidelines Subcommittee. 1999 World Health Organization-International Society of
Hypertension guidelines for the management of hypertension. J Hypertens. 1999; 17: 151-183.
De Backer TLM, De Buyzere M, Segers P, Carlier S, De Sutter J, Van de Velde C, De Backer G.
The role of whole blood viscosity in premature coronary artery disease in women.
Atherosclerosis 2002; 165: 367-73
Jonsson G, Fossum E, Kjeldsen S E, Høieggen A, Os I, Eide I, Westeheim A. Lower plasma
noradrenaline and blood viscosity on carvedilol vs atenolol in men with recent myocardial
infarction. Blood Pressure 2002; 11: 377-384.
Final version 7.12 2 June 2004
24
Kuller LH, Tracy RP, Shaten J, Meilahn EN. Relation of C-reactive protein and coronary heart
disease in MRFIT nested case-control study. Multiple Risk Factor Intervention Trial. Am J
Epidemiol. 1996; 144: 537-547
Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the
risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997; 336: 973-979
Ross R. Atherosclerosis-an inflammatory disease. N Engl J Med. 1999; 340: 115-126
Bakris GL. Microalbuminuria: prognostic implications. Curr Opin Nephrol Hypertens. 1996; 5:
219-223.
Dinneen SF, Gerstein HC. The association of microalbuminuria and mortality in non-insulindependent diabetes mellitus: a systematic overview of the literature. Arch Intern Med. 1997; 157:
1413-1418.
Parving HH. Et al, The effect of irbesartan on the development of diabetic nephropathy in
patients with type 2 diabetes. N Engl J Med. 2001; 345: 870-878
Lewis E. at al, Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients
with nephropathy due to type 2 diabetes. N Engl J Med. 2001; 345: 851-860
Brenner, B M et al, Effects of losartan on renal and cardiovascular outcomes in patients with
type 2 diabetes and nephropathy. N Engl J Med. 2001; 345: 861-869
ADA recommendations. Diabetes Care. 2002;25: Suppl 1
Socialstyrelsen, State of the Art; Diabetesnefropati 1998
Kjeldsen SE, Jamerson K, Julius S, Hedner T, Pehrsson N-G. Characteristics of reversed office
hypertension – May treatment resistant home hypertension be explained by smoking?
Abstract ESH Paris June 13-17, 2004.
Sjöholm Å, Nyström T. Kronisk inflammation kan orsaka typ-diabetes. Läkartidningen 2004;
101: 1716-1721
Hussain MA, Puniyani RR. Relationship between Power Law Coefficients and Major Blood
Constituents Affecting the Whole Blood Viscosity. Journal of Biosciences 1999; 24(3): 329-337
Kirwan JR, Chaput de Saintonge M, Joyce CRB. Clinical Judgement analysis. Quaterly J Med.
1990, Series 76, No 281, pp 935-949
Final version 7.12 2 June 2004
GLOSSARY AND ABBREVIATIONS
RIAHD
Risk Factor Assessment in Hypertension and Diabetes
ESH
European Society of Hypertension
ESC
European Society of Cardiology
SCORE
Systematic Coronary Risk Evaluation
RF
Risk Factor
ACC
Associated Clinical condition
TOD
Target Organ Damage
BP
Blood Pressure
BPM
Blood Pressure Measurement
IDDM
Insulin Dependent Diabetes Mellitus
NIDDM
Non Insulin Dependent Diabetes Mellitus
CV
Cardiovascular
AIIRA
Angiotensin II Receptor Antagonists
25
Final version 7.12 2 June 2004
Appendices
Appendix 1
Study Organisation
Appendix 2
Study sites (Investigators and study nurses)
Appendix 3
Study Flow
Appendix 4
Study organisation Chart
Appendix 5
RIAHD screening (High risk and low risk groups)
Appendix 6
CRF
Appendix 7
Laboratory and blood sampling routines
Appendix 8
SAE report
Appendix 9
Patient informed consent
26
Final version 7.12 2 June 2004
27
Appendix 1
Study Organization And Participating Clinical Sites
Steering Committee
Thomas Hedner
(chair)
Thomas Leoo
Anders Niklason
Ola Samuelsson
Per-Anders Jansson
Stanko Skrtic
LiMing Gan
Per Boström
RIADH working
group
Thomas Hedner
Thomas Leoo
Anders Niklason
Per Boström
Expert reference
group
Leo Niskanen
Sverre Kjeldsen
Statistics
Telephone
Facsimile
e-mail
031-342 2974
031-419368
[email protected]
08-470 1877
08-470 1848
[email protected]
031-342 29 40
031-82 67 23
[email protected]
08-470 1875
08-470 1848
[email protected]
Final version 7.12 2 June 2004
Appendix 2
Study sites (Investigators and study nurses)
28
Final version 7.12 2 June 2004
29
Appendix 3
Study Flow
RIAHD Screening
Mareld
Ca. 10 000 DM
without MA
13 000 DM patients
Screened for MA
Create routines and do
risk assessment
RIAHD
Matched Controls
(Hypertensive patients,
no DM or MA)
Ca. 3000 DM
with HT+MA
500
500
RIAHD Study
RIAHD
500 hypertensive high risk patients (DM&MA)
500 hypertensive low risk patients (no DM or MA)
Risk evaluation and riskfactor identification
Screening &
Visit
Patient evaluation
Blood samples
Standard Lab
Blood viscosity
Inflammatory blood markers
RF, ACC and TOD according to ESH/ESC
Health economics
Clinical judgement physician & patient
Home Blood Pressure
Planned follow-up
Patient 5 yrs follow-up
for endpoint
Final version 7.12 2 June 2004
30
Appendix 4
Study organisation chart
Study support
Sv Hypertoniföreningen
L Hanssons minnesfond
Sponsors
Bristol-Myers Squibb
Sanofi Synthelabo
Sponsors
Study management
& Study secretariat
Site selection
Site set up
Monitoring
Steering committee
Planning
Study sites
Screening
Enrolment
Evaluations
CRF
Patients
Home BP
Questionnaires
LAB
Data Management
Endpoint
committee
Endpoint
evaluation
Only for 5 yrs
follow-up
Final version 7.12 2 June 2004
31
Appendix 5
RIAHD screening
The RIAHD HIGH RISK GROUP
 Informed Consent
Negative->out
 Screening for Hypertension.Treated Hypertension Positive - go on screening for Diabetes
Negative->out
 Screening For Diabetes. Known treated Diabetes
Positive - go on screening for
microalbuminuria
 Enrolment requires two positive samples with a three month interval as in the Mareld
screening and a verifying quantitative measurement
Negative ->out
Negative ->out
Mareld
Screening
Positive
New screening
after 3 months
Negative->out
Positive
= MA
A verifying quantitative
measurement
Positive
enrollment in RIAHD High risk
group
Final version 7.12 2 June 2004
32
Appendix 5, cont.
RIAHD Screening
The RIAHD LOW RISK GROUP
Negative->out
 Age and gender matched with a patient from RIADH High Risk Group
Positive – go to screening
 Informed Consent
Negative->out
 Screening for Hypertension. Treated Hypertension Positive – Next step exclusion of
Diabetes
Elevated->out
 Exclusion of diabetes. fS glucose test
Normal - Next step exclusion of
microalbuminuria
 Exclusion of Microalbuminuria
Negative
enrollment in RIAHD Low Risk
Group
Positive ->out
Microalbuminuria screening procedures
Reagent strips; Micral tests® Roche
Packaging; Micral test sticks Clinic by the Sponsors.
Storage conditions; Reagent strips should be stored at room temperature between 15-30°C (59°86°F). Products must not be used after expiration date and bottles must not be stored in direct
sunlight.
Explanation for use; Reagent test areas on the Reagent strips are ready to use upon removal
from the bottle and the entire reagent strip is disposable.
The strips are read visually, requiring no additional laboratory equipment. The directions must
be followed exactly. The reagent strips must be kept in the bottle with the cap tightly closed to
maintain reagent reactivity. To obtain optimal results, testing should be done on fresh urine.
Investigational reagent accountability; Study representatives will check with each site to ensure
an adequate supply of the reagents is provided to the Clinic.
Final version 7.12 2 June 2004
Appendix 7
Laboratory and blood sampling routines
According to protocol specifications and choosen routine laboratory .
33
Final version 7.12 2 June 2004
Appendix 8
SAE Report
34