returnNICE-study
Diabetes, as well as hypertension
and hyperlipemia, is a serious risk factor for arteriosclerosis and
cardiovascular diseases, and its effect on mortality has been
demonstrated. In addition, the incidence
of diabetes is high in many countries worldwide, and the burden of this
illness
on society is enormous.
The purpose of diabetes treatment
is to suppress development of not only 1) microangiopathy and its three
main
complications (nephropathy, retinopathy and neuropathy) but also 2)
organ
disorders due to the progress of arteriosclerosis, and thus prevent
cardiovascular
complications and death. In the past 20
years, studies on the cause and state of diabetes, studies on
therapeutic
efficacy for diabetes and studies on epidemiology of diabetes have been
performed actively. As a result, the
importance
of more effective and efficient control of blood sugar at the
physiological
level has been demonstrated. Up to date
information regarding blood sugar control has been provided as a
guideline to
physicians all over the world by the World Health Organization (WHO),
American
Diabetes Association (ADA), and others.
In Japan, the Japanese Diabetes Society has prepared guidelines
for the
treatment of diabetes in consideration of a Japanese specific
life-style and
the incidence of complications.
A survey shows that the most
frequently observed direct cause of death in diabetic patients is
cardiovascular disorder. However,
investigations and surveys such as DCCT, UKPDS and KUMAMOTO-study, etc.
clarified that strict control of blood sugar level prevented
development and progress
of diabetic microangiopathy, but could not show a significant effect on
great
vessel disorder. Recently, the
DECODA-study,
DECODE-study and Honolulu-study have demonstrated that postprandial
high blood
sugar is involved in great vessel disorder. Therefore,
possible prevention of great vessel
disorder in diabetic patients is suggested by improving the
postprandial blood
sugar level as achieved using ultrarapid-acting type insulin, which has
become
available recently. Even with results in
Europe and the US obtained, the life-style and incidence of
complications in
Japanese people are different, and there are many points that remain
uncertain with
respect to the direct application of foreign results to Japanese people. Therefore, in Japan also, it is necessary to
conduct a large-scale clinical study and to establish high-level
evidence using
mainly Japanese people through hospitals having many patients.
Taking these existing
circumstances into consideration, for the purpose of comparing efficacy
of
intensive therapy between 1) ultrarapid-acting type insulin (insulin
aspart)
and 2) conventional regular-acting type insulin (R), a Multicenter Open
Label
Randomized Controlled Trial was planned in Japan using the occurrence
of
cardiovascular events in patients with diabetes, a high risk factor, as
an
index.
2. Investigational drugs
1) Ultrarapid-acting type insulin: Insulin aspart
2) Regular-acting type insulin: Penfill R, Humacart R, etc. (vial, pen or kit can be used.)
When needed, middle type,
slow-acting
type, and sustained-acting type insulin can be used concomitantly.
3. Subjects
3.1 Subjects
Subjects are patients with type 2 diabetes satisfying the following criteria.
3.2 Inclusion criteria
Subjects are patients satisfying the following conditions
1) – 3).
1) Outpatients and inpatients aged 20 years or more but younger than 85 years. Men or women.
2) Patients with type 2 diabetes based on the diagnostic standard of the Japanese Diabetes Society
3) No specific restriction on the current treatment. Patients having switched treatment are also accepted.
3.3 Exclusion criteria
1) Patients with type 1 diabetes
2) Patients with a past history of cerebral angiopathy (cerebral hemorrhage, cerebral infarction, transient cerebral ischemic attack, subarachnoid hemorrhage, etc.) within 6 months before giving consent
3) Patients with a past history of myocardial infarction within 6 months before giving consent
4) Patients planning to receive PTCA or CABG, or who had PTCA or CABG within 6 months before giving consent
5) Patients with coronary arteriopathy (angina pectoris, etc.) that requires treatment with β-blocker or calcium-antagonist
6) Patients with atrial fibrillation or atrial flutter
7) Patients with renal dysfunction (serum creatinine ≥ 3.0 mg/dL)
8) Patients with liver dysfunction (AST, ALT ≥ 100 IU/L)
9) Patients with a past history or suspected of having a malignant tumor within 5 years before giving consent
10) Pregnant or possibly pregnant patients
11) Other patients judged inappropriate for the study by the investigators (patients presenting difficulty in frequently receiving rapid-acting type insulin or ultrarapid-acting type insulin therapy, including patients’ compliance with treatment)
4. Patients’ consent
Before registration, investigators
must explain the following contents of this trial to the patients so as
to
obtain consent for participation in this trial from the subjects. (This must be performed in accordance with
the ethical code of each hospital. A
written
consent form must be prepared although each hospital may use its own
form.)
1) The purpose of this trial is to examine the extent to which development (recurrence) of cardiovascular complication can be prevented.
2) The period of administration of allocated drug ends in March 2008. One of two types of drugs, ultrarapid-acting type insulin (insulin aspart) or conventional rapid-acting type insulin is used. Middle type, slow-acting type, sustained-acting type insulin can be used concomitantly when needed.
3) Drugs are allocated at random.
4) Other therapeutic methods are available.
5) Participation in this trial is not enforced. No subject shall be placed at a disadvantage if he/she does not participate in the trial.
6) The subject may withdraw from the trial at any time after participation.
7) Even when use of allocated drug is discontinued, the course thereafter will be surveyed.
8) Privacy is protected.
5. Study design
This study is designed as an Open
Label Randomized Controlled Trial using the following 2 groups.
1) UR (ultrarapid-acting type insulin) group: Insulin aspart, 3 times/day
2) R3 (rapid-acting type insulin) group: *Rapid-acting type insulin, 3 times/day
*
Any
product can be used as the rapid acting insulin.
In both groups, middle type, slow-acting type, and sustained-acting
type
insulin may also be used concomitantly.
6. Registration of patients
6.1 Registration
Investigators should register the following items for patients who satisfied the inclusion criteria and did not infringe on the exclusion criteria at the EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital by sending the registration sheet directly or via internet (E-mail).
1) Date of entry into registration sheet, name of physician in charge, name of clinical department and medical institution, date of consent obtained, Chart No., patient’s initials, sex, presence or absence of pregnancy and menopause, birth date, and outpatient or inpatient status
2) Blood sugar level at the time of registration, blood sugar level at 90 minutes after meal (if possible), HbA1c, 1-5AG (if possible)
3) Cardiovascular risk factor as the inclusion criteria
4) Exclusion criteria check
5) Patient’s background: height and body weight, time when diabetes was indicated, family history of hypertension, smoking, habitual drinking, complication, past history of diseases (other than cardiovascular risk factor as the inclusion criteria)
6)
Examinations:
If examinations shown in 7) and 8) were not performed within 3 months
before
registration, they should be performed by the time of registration. Examinations 9)-13) should be added at the
appropriate
time.
7)
Clinical
laboratory tests:
(Fasting blood sugar), blood sugar at 90 minutes after meal, HbA1c,
(1-5AG),
serum creatinine, total cholesterol or (LDL-cholesterol), triglyceride,
HDL-cholesterol, urinary protein, urinary trace albumin/urinary
creatinine
8) Examination of ocular fundus (NDR, SDR, prePDR, PDR), irradiated with laser or not
8) Electrocardiography
9) Chest roentgenography (*at institutions where possible only)
10) Carotid IMT (*at institutions where possible only)
11) PWV (pulse wave velocity), ABI (=API) (*at institutions where possible only)
12) State of disease at the time of registration for patients with a past history or complication of cardiovascular diseases (myocardial infarction, angina pectoris, apoplexy, transient cerebral ischemic attack, arteriosclerotic peripheral arterial occlusion)
13) Presence or absence of neuropathy (MCV, SCV, f wave: on the basis of left median nerve) (*at institutions where possible only)
6.2 Drug allocation
Investigators should allocate drugs at random using the envelope method. The number of target cases should be reported to the EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital beforehand, envelopes for allocation corresponding to the number of subjects should be sent to investigators, and investigators should allocate at random.
Until the start of administration of allocated drugs, blood-sugar reducing treatment should be continued according to the current therapeutic method. After the start of administration of allocated drug, concomitant use of other blood-sugar reducing drugs is prohibited, as a rule (glibenclamide, gliclazide, glimepiride, acarbose, voglibose, thiazolidine drugs, and biguanid drugs).
7. Target level of blood sugar control and dosage
7.1 Target level of blood sugar control
Fasting blood sugar level of 126 mg/dL or less and HbA1c of 6.5% or less should be targeted.
In the UR group, postprandial blood sugar level (after 90 minutes) should be targeted at 180 mg/dL or less each time.
7.2 Dosage of allocated drug
The investigator is allowed give judgment on the change of dosage so as to control blood sugar at the aforesaid target level.
Tapering or discontinuation of insulin is allowed when needed. Such cases must be reported.
7.3 Concomitant drug, etc.
1) Permissible concomitant drugs: Drugs other than those for which concomitant use is allowed under the above specified conditions can be administered freely.
2) Combined therapy: Combined therapies together with general diet therapy, exercise therapy, smoking cessation, etc. are not particularly restricted.
8. Survey period
The survey period is from
registration of each subject patient until March 2008.
At this point, extension of the period will
be considered after consultation.
9. Evaluation
The Event Evaluation Committee
(refer to “17.8”) should evaluate the following evaluation items, by
blind drug
allocation.
9.1 Primary endpoints
Cardiovascular events (event that occurs earliest among the following events)
1) Sudden death: Natural death within 24 hours after development of acute symptoms.
2) Brain: New development or recurrence of apoplexy or transient cerebral ischemic attack (refer to the following diagnostic criteria)
3) Heart: New development or recurrence of acute myocardial infarction, and new development, aggravation or recurrence of angina pectoris (refer to the following diagnostic criteria)
4) Newly developed ASO, amputation of leg due to ASO, arteriosclerotic peripheral arterial occlusion (Grade 2 or above of Fontaine Classification: Refer to the following diagnostic criteria)
Diagnosis
of transient cerebral ischemic attack (TIA)
1.
Local
related signs of TIA disappear completely within 24 hours (within 1
hour in
many cases).
2.
Attack
occurs suddenly (within 2 or 3 minutes in many cases).
3.
Signs
a)
TIA
of internal carotid arterial system
(1)
Signs
develop on the unilateral side of the body (dyskinesia, sensory
disorder,
unilateral impairment or loss of visual acuity, aphasia, etc.)
(2)
The
number of attacks is small, and the signs at each attack are similar.
(3)
Cerebral
infarction tends to develop.
b)
TIA
of vertebral-basilar arterial system
(1)
Various
signs develop on the bilateral or
unilateral side of the body.
(2)
Cerebronervous
signs (double vision, dizziness, dysphagia, bilateral loss of visual
acuity,
hemianopia, etc.)
(3)
The
number of attacks is large, and the signs at each attack are different.
(4)
Cerebral
infarction only develops a little.
4.
Development
of mere dizziness is not diagnosed as TIA.
1.
Kinesalgia
attack (chest pain, feeling of tightening in the chest, etc.) for which
rapid-acting nitrate drugs such as nitroglycerine are effective and
which occurs
at the time of exertion or rest.
2.
Upon
electrocardiogram during attack or exercise-loading, significant
ischemic ST
change is observed.
Occlusive
arteriosclerosis Fontaine classification
|
Grade 1: Cold sensation and
numbness of extremities |
Grade 3: Pain at rest |
|
Grade 2: Intermittent limping |
Grade 4: Ulceration/necrosis
of fingers and toes |
1)
Aggravation
of diabetic retinopathy
2) Aggravation of diabetic nephropathy: Doubling of serum creatinine (2.0 mg/dL or less is not regarded as an event), serum creatinine ≥4.0 mg/dL, ESRD (end-stage renal disease: shifting toward dialysis, kidney transplantation, etc.)
3) Changes in MCV, SCV and f wave
4) Total mortality
5)
Changes
in the mean IMT of common carotid arteries
*max IMT (a) bilateral sides are 1 cm and
(b, c), (a+b+c)/3
6) Changes in the pulse wave velocity (PWV) (rt & 1t baPWV), ABI
7)
Rate
of withdrawal from insulin
10. Survey items
Perform surveys as follows.
1) Survey every 6 months
2) Survey at the time of discontinuation/dropout
3) Survey of cardiovascular events
4) Survey of adverse events
5) Comment, etc., and items of correspondence
10.1 [Survey every 6 months]
Every
6 months from the start of administration, information regarding the
following
items obtained during the study period should be sent to the EBM
Center,
Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai
Nakatsu
Hospital by FAX or mail.
10.1.1 Drugs
Allocated drugs
1) Drug name, daily dose and the state of injection
2) Concomitant drugs: use or non-use of concomitant drugs, drug name, daily dose, period of concomitant use
*
Only
drugs that may be involved in the course such as hypotensor,
cardiotonic agent,
antithrombotic drug, drugs for angina pectoris, antiarrhythmic agents,
anti-hyperlipemic agents, adrenocortical steroids and drugs for
treatment of
gout/hyperuricemia.
10.1.2 Test
items
1)
Blood
sugar (90 minutes after meal), HbA1c, as required.
(1-5AG and fasting blood sugar should be measured at institutions where
possible only.)
2)
Other
clinical laboratory tests: Serum
creatinine, total cholesterol, triglyceride, HDL-cholesterol, urinary
protein
(qualitative), urinary trace albumin/urinary creatinine
10.1.3 Adverse
events
When adverse events develop, Form 4 [Adverse event survey sheet, abnormal changes of clinical laboratory values] in which the following contents are entered should be sent by FAX or mail (Report cardiovascular events as 10.3).
Name of adverse event (items of subjective symptoms, items of objective signs, items of abnormal change of clinical laboratory value), serious or not, the value when abnormal change of clinical laboratory value is found, causal relation to the allocated drug, and comment*
*:
Perform
follow-up survey as much as possible.
|
Adverse events refer to all
untoward clinical events (including abnormal changes in clinical
laboratory tests) that develop in patients treated with the drugs. Among these, events for which relation to the
drugs cannot be negated are considered adverse reactions. |
[Judgment on causal relationship and criteria]
1) Relation can be negated: When there is no correlation in terms of time, or when the event can be considered attributable to other causes such as a primary disease, complication, concomitant drug or combined treatment;
2)
Relation
cannot be negated: In the case when an
event does not come under the definition of “Relation can be negated”
(including cases of insufficient material for evaluation);
10.2 [Yearly survey]
In addition to the items in the survey every 6 months, tests for the following items should be performed, and the results should be entered into the internet survey format yearly, and sent.
10.2.1 Tests
added to the items of the 6 months
survey
1) Electrocardiography
2) Funduscopy
2) IMT (at institutions where possible only)
3) PWV (at institutions where possible only)
4) Chest roentgenography (at institutions where possible only)
5)
Nerve
findings (MCV, SCV and F wave of left median nerve:
at institutions where possible only)
10.3 [Survey at the time of occurrence of cardiovascular event]
When cardiovascular events occur, Form 5 [Survey sheet of cardiovascular events in detail] in which the following contents are entered should be sent immediately by FAX or mail.
10.3.1 Cardiovascular
events
Event name, date of occurrence, treatment, outcome and comment*
* Perform follow-up survey until recovery or until the end of the clinical trial (March 2008) as much as possible. Record the values (changes) of related test items also.
Sudden death : Natural death within 24 hours after development of acute symptoms.
Brain : New development or recurrence of apoplexy or transient cerebral ischemic attack
Heart : New development or recurrence of acute myocardial infarction, and new development, aggravation or recurrence of heart failure and angina pectoris
Blood vessel : New development or aggravation of arteriosclerotic peripheral arterial occlusion
Death due to causes other than cardiovascular events
10.3.2 Details
of cardiovascular events
For each event, subjective symptoms, objective signs, course, clinical laboratory values, roentgenogram, electrocardiogram, electrocardiogram upon exercise loading, echo-cardiogram, angiogram, CT, MRI, etc. that can serve as a basis for judgment
10.3.3 Nephropathy
and retinopathy events
1) Nephropathy: Doubling of serum creatinine (2.0 mg/dL or less is not regarded as an event), serum creatinine ≥ 4.0 mg/dL, ESRD (shifting toward dialysis, kidney transplantation, etc.)
2) Hemorrhage in ocular fundus, irradiation with laser
10.4 [Survey at the time of discontinuation/dropout]
When use of allocated drug is discontinued, or a patient does not show up for a long time, Form 6 [Survey sheet for discontinuation/dropout] in which the following contents are entered should be sent immediately to the EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital by FAX or mail.
10.4.1 Discontinuation/dropout
Classification of discontinuation/dropout, reason for discontinuation/dropout, date of discontinuation/dropout and comment
1) Discontinuation: When administration of allocated drug is discontinued owing to a medical decision by the investigator or upon request of patient;
2) Dropout: When a patient has withdrawn consent or does not show up;
3) Reason for discontinuation: (1) Cardiovascular event, (2) Adverse event (including excessive hypotension), (3) Insufficient blood sugar control, (4) Others
4) Reason for dropout: (1) Withdrawal of consent, (2) Not visiting hospital (including transfer to another hospital), (3) Others
When a patient does not show up, examine the present condition of the patient by phone or mail. As a result, when occurrence of an adverse event or cardiovascular event is found, send the concerned survey sheet to the EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital by internet.
10.5 [Survey of comment, etc. and items of correspondence]
If there are comments or items of correspondence, send Form 7 [Sheet for comment, etc. and items of correspondence] to the EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital by FAX or mail. Refer to the survey sheet for details.
[Survey
schedule]
|
|
Registration |
Every 6 months |
Once a year |
... |
Discontinuation/dropout Occurrence of event |
|
Patient’s background |
¤ |
|
|
|
|
|
Survey of drugs |
¤ |
¤ |
¤ |
... |
¤ |
|
HbA1c, |
¤ |
¤ |
¤ |
... |
¤ |
|
blood sugar 90 minutes after
meal |
¤ |
¤ |
¤ |
|
|
|
*Fasting blood sugar |
¡ |
¡ |
¡ |
|
|
|
*1-5AG |
¡ |
¡ |
¡ |
|
|
|
Clinical laboratory test** |
l |
|
l |
... |
l |
|
Electrocardiography |
l |
|
l |
|
l |
|
Chest roentgenography |
¡ |
|
¡ |
... |
|
|
IMT |
¡ |
|
¡ |
... |
|
|
PWV |
¡ |
|
¡ |
|
|
¤:
Required
l:
Unnecessary when test values within 3
months before registration are available
¡:
At institutions where possible only (unnecessary
when test values within 3 months before registration are available)
*
Ask patients to come
to the hospital so that the 90-min test is possible.
* Perform 1-5AG test as much as possible.
11.Number of subjects required
According to various types of
results reported, the incidence of cardiovascular events in Group R3
was
estimated at 60 events/1000 persons/year.
We believe the incidence reducing effect in Group UR to be 40%.
In this trial, assuming that the
planned registration period is 1 year, the follow-up period after the
end of the
registration period is 3 years, and the rate of subjects for whom
follow-up may
become impossible in the entire trial period is 20%. The necessary
number of
subjects for registration is calculated to be about 250 per group, with
a total
of 500 subjects, at an alpha level of two-sided 5% and a power of test
of
90%. Even when estimation of the
incidence of events in Group UR or that of the rate of decrease of
incidence of
events in Group R3 is incorrect, 70-80% of the power of test can be
secured if
500 subjects are registered.
On the basis of these results, the
target is to register at least 500 subjects, preferably 600 subjects,
in a
registration period of 1 and a half years.
As the indexes of early stage
arteriosclerosis, concerning IMT, a sufficient and significant
difference
(p<0.05) can be obtained with 100 subjects per group at a difference
of 0.1
mm (SD=0.2) after 5 years. Concerning
PWV also, sufficient significant difference (p<0.05) at 1000 cm/s v.
s. 900
cm/s (SD=200) can be obtained with 100 subjects per group.
12. Analysis
12.1 Population of analytical target
Perform analysis of all the
registered and allocated participating subjects as the population of
analytical
target based on the principle of intention-to-treat, regardless of the
actual state
of injection of the drug, or changes in drugs during the period, etc.
12.2 Interim analysis
One year after the completion of
registration, perform an interim analysis for the purpose of comparing
the
incidence of cardiovascular events, the primary endpoint (refer to Item
of
9.1), between Groups UR and R3. Report
the results of the interim analysis only to the Independent Monitoring
Committee. On the basis of the results
of the interim analysis, the Independent Monitoring Committee should
give a
recommendation to the trial-conducting organization concerning
discontinuation
or continuation of the trial and amendment to the protocol.
In testing, use two-sided 5% as
the alpha level. In the arrangement for
conducting the interim analysis, use the O’Brien-Fleming type Alpha
Consumption
Function.
12.3 Main analysis
12.3.1 Primary
endpoint
Compare the incidence of
cardiovascular events, the primary endpoint (Item of 9.1), between
Groups UR
and R3. Perform analysis using the
presence or absence of a diabetic complication as used for group
allocation. Perform the stratified log
rank test to examine the incidence of events, and draw a survival curve
using
the Kaplan-Meier method. Obtain the
ratio of incidence of events and the confidence interval in 2 simple
groups by
stratified Cox regression, then extract the reducing effect on the
incidence of
events, and report. As the confidence
coefficient for obtaining the alpha level and confidence interval, use
the
value obtained by the alpha consumption function
12.3.2 Secondary
endpoints
Among the secondary endpoints
shown in Item 9.2, analyze the incidence of events in a similar manner
to that
for the primary endpoints. Concerning
the shrinking of the early stage arteriosclerosis indexes (IMT, PWV),
perform
comparison between Groups UR and R3 only for investigation. For the rate of withdrawal from the allocated
treatment, obtain the difference in the rate between the 2 groups, and
the
confidence interval. In every analysis,
use two-sided 5% for the alpha level and a two-sided 95% confidence
interval.
12.4 Secondary analysis
Concerning the events among the
primary endpoints and the secondary endpoints, perform Cox regression
arranged
by cardiovascular risk factors described by sex, age and inclusion
criteria (Item
3.2), and obtain the reducing effect on the incidence of events and the
95%
confidence interval in Groups UR and R3
12.5 Investigative
analysis by means of sub-study
For efficient utilization of the
data in this study, the data will be available to persons related to
this study
(members of various committees, corporate investigators, etc.), and
sub-studies
will be conducted. Items for which any
strong
conclusion can be reached based on the data of this study are limited
to the
primary endpoints only. Therefore, all
the sub-study items are ranked as investigational items, and analysis
will be
performed at the EBM Center, Department of Diabetes and Endocrine
Medicine of
the Osaka-fu Saiseikai Nakatsu Hospital.
When a person wants to conduct a sub-study
using the data of this study, they must summarize the contents of
investigation
in Form 8 [Concept sheet] and submit this form to the EBM Center,
Department of
Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu
Hospital. As regards the contents of the
proposed
sub-study and the method for conducting such study, this shall be
examined by
the EBM Center, Department of Diabetes and Endocrine Medicine of the
Osaka-fu
Saiseikai Nakatsu Hospital together with the person proposing such
study.
13. Clinical expenses
Since the tests and drug
administration in this study are performed within the range of routine
medical
services, expenses should be covered by health insurance
14. Measures against health hazards
The insulin products used in this study
are marketed drugs at present.
Therefore, when a serious adverse reaction develops in a patient
receiving
doses stipulated in this study under the instruction of the
investigator, the
patient can apply for relief payment according to the system for drug
ADR
relief.
Treatment of other adverse
reactions should be covered by heath insurance
15. Study duration
April 2002-March 2008
(registration period: January 2002-July
2003
16. Amendment to protocol
When a change in the protocol of
the on-going study becomes inevitable, or when the Independent Data
Monitoring
Committee recommends a change in the protocol, the representative of
this study
should direct the Protocol Committee to prepare a draft of the
revision, and
should obtain approval of the results by the Operating Committee.
17. Organization of study −A total of 11 institutions− (draft)
17.1 Manager
Haruo Nishimura
Osaka Saiseikai Nakatsu Hospital
(Responsible for
operating the study, and
making adjustments among the several committees for smooth performance
of the
study.)
17.2 Study Director
Dr. Koji Maeda
Osaka Saiseikai Nakatsu Hospital
17.3 Special Consultant
Dr. Hideshi
Kuzuya
Kyoto National Hospital
Dr. Shigeo Nishi
Japanese Red Cross Society, Wakayama
Medical Center
Dr.Ikuko Hanaoka Japanese Red Cross Society, Wakayama Medical Center
Dr. Yasuhito Baba
Yodogawa Christian Hospital
(They give advice
to the representative of this
study concerning smooth performance of the study.)
17.4 Operating Committee
Dr. Kuzuya
Kyoto National Hospital
Dr. Yamamoto
Japanese Red Cross Society, Wakayama
Medical Center
Dr. Fukuda
Fukuda Clinic
Dr. Ohasi
Komatsu
Hospital
Dr. Mori
Komatsu
Hospital
Dr. Kato
Kishiwada
Citizen’s Hospital
Dr. Okuda
Okuda
Clinic
Dr. Maeda
Maeda
Clinic for Internal Medicine
Dr. Shintani
Osaka-fu Saiseikai Nakatsu Hospital
Dr. Kentaro Otochi Otoshi Clinic
(This committee
prepares the protocol,
survey sheet, consent form, etc., and performs operation and control of
the
study. All final decisions necessary for
operating the study should be made by this committee.)
17.5 Promotion Committee
Yukie Oka Department
of Diabetes and Endocrine Medicine of the
Osaka-fu Saiseikai Nakatsu Hospital
(For smooth
conduct of registration of study
participants, this committee is in charge of contact between the
Operating
Committee and Participant Institutions.)
17.6 Protocol Preparation Committee
Haruo Nishimura Department of Diabetes and
Endocrine Medicine of the Osaka
Saiseikai Nakatsu Hospital
Koji Maeda
Department of Diabetes and Endocrine Medicine of the
Osaka Saiseikai Nakatsu Hospital
Mitsuyo Shintani Department of
Diabetes and Endocrine Medicine of the Osaka
Saiseikai Nakatsu Hospital
(This committee
prepares the draft for the
protocol, survey sheet, consent form, etc.
When revision of the protocol, consent from, etc. is required,
this
committee will prepare the draft of revision according to the
directions of the
Operating Committee.)
17.7 Event Evaluation Committee
Dr. Okuda
Okuda
Clinic
(On the basis of
the “Evaluation criteria for
cardiovascular events” stipulated by this Committee, evaluation of
cardiovascular events is performed under a blind drug allocation group.)
17.8 Study Statistician
EBM Center,
Department of Diabetes and Endocrine
Medicine of the Osaka-fu Saiseikai Nakatsu Hospital
EBM Center is responsible for the statistical
aspect of this study, and prepares the “analytical protocol”, “protocol
for
interim analysis”, etc. Interim analysis
and final analysis are performed.
17.9 EBM Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu Saiseikai Nakatsu Hospital
Statistical analysis wa independently performed by Doshisya University, Faculty of Culture and Information Science (Kyoto, Japan).
EBM Center takes on the
responsibility of functioning as the central office in charge of
adjustment in
the schedule of several committee meetings, preparation for meetings,
preparation of documents, conducting office work pertaining to
accounting for
participant institutions and committee members, etc.
The center supports registration business
such as registration of patients and allocation of drugs, grasps the
state of
study progress, and performs data management such as control and
quality assurance
for the study. When a problem occurs in
the
operation of the study, this center will suggest a method for
improvement, and
execute such method in accordance to instructions by the Operating
Committee.
17.10 Independent Data-Monitoring Committee
Dr. Makoto Ohtoshi Chairman of Academic
Committee, Osaka-fu, Kita-ku Medical
Association, and Ohtoshi Clinic of Internal Medicine
(From the standpoint of a third
party, this committee examines the scientific and ethical validity of
the
protocol. Furthermore, this committee
monitors whether the study is being conducted appropriately, and
recommends
necessary improvement to the Operating Committee when needed. In the interim analysis, if continuation of
the study is judged to be ethically problematic from the viewpoint of
safety
and efficacy, this committee should recommend to discontinue the study
to the
representative of this study.)
Correspondence
Haruo
Nishimura
EBM
Center, Department of Diabetes and Endocrine Medicine of the Osaka-fu
Saiseikai
Nakatsu Hospital
10-39,
Shibata 2-chome, Kita-ku, Osaka-shi
530-0012
TEL
06-6372-0333 (switchboard number)
070-6286-7024 (Nishimura: cell phone)
FAX:
06-6372-0339
*
EBM Center is a NPO organization, and profit is not sought.
*
Necessary expenses are supported by the Osaka-fu Saiseikai Nakatsu
Hospital,
patients’ association, and others.
NICE-study
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At start of
study |
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At 0, 12, 24, 36, 48, 60 months |
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At 6, 18, 30, 42, 54 months |
|
|
|
|
|
|
|
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Consent |