MANUAL OF OPERATION
with Multi-Vessel Disease– 2– India Study
(TUXEDO-2-India)
MANUAL OF OPERATIONS
TABLE OF CONTENTS
01. CONTACTS, HELPLINE
2.1 General duties………………………………………………………………………………….6-7
2.2 Selection of clinical investigators and
sites…………………………………………..……… ….7
2.3 Training of investigator and site personnel and site
monitoring…………………….…........ ......7
2.4 Documentation……………………………………………………………………………… …..7
2.5 Insurance………………………………………………………………………………................7
03.1 Overview of Site Activation
Requirements………………………………………….................8
03.2 Training of Study Site
Personnel…………………………………………………….................8
03.2.1 Protocol-Specific Training……………………………………………………………………9
03.2.2 ICH-GCP Training……………………………………………………………………………9
03.4 Overview of Requirements for Implementation of Protocol
Amendments……………….........9
04. RECRUITMENT, SCREENING AND
RANDOMIZATION………………….………........9
04.1. Screening Process……………………………………………………………………………...9
04.2. Screening Log………………………………………………………….………….…………..9
04.1.1 Inclusion
Criteria………………..…………………………………………………….....10-12
04.1.2 Exclusion
Criteria…………...…………………………………………………………...12-13
RANDOMIZATION……………………………………………………………………….……..14
04.3. SCREENING TO RANDOMIZATION VISITS………………………………………….17
TUXEDO-2-INDIA Page 3 of 40
04.3.1 Angina Status …………………………………………………………………………...17-18
05.1 Invasive Procedures…………………………………………………………………………...20
05.3 Pre and Post-Procedure ECGs………………….……………………………………………..20
06. SCREEN FAILURES……………………………………………………………………… ..21
10. TIMELINE AND VISIT SCHEDULE ……………………………………………………...27
11.TRIAL ADHERENCE AND RETENTION…………………………………………………28
11.1 Maximize Availability of Staff
………………………………………………………………28
12. RECORD-KEEPING AND COMMUNICATION…………………………………………28
12.1 Overall retention………………………………………………………………………….…..28
12.2 Participants unable to contact, lost to follow up and
withdrawals……………….……….28-29
13. TREATMENT STRATEGIES……………………………………………………..………..29
13.1.1 Overview of Optimal Medical
Therapy………………………………………….…………29
13.1.2 Anti-Platelet Therapy……………………………………………………………………….29
13.1.3 Angina Management………………………………………………………………………..29
13.1.4 Hypertension Management…………………………………………..……………………..29
13.1.5 Diabetes
Management………………………………………………………….……......29-30
13.1.6 Lipid Management………………………………………….……………….……………...30
14. STUDY COMPLIANCE…………………………………….……………………………….31
14.2 Protocol Deviation/Violation Reporting
Requirements………….………………………..31-32
15. SERIOUS ADVERSE EVENT………………………………………………..….………….32
15.1 SAE Reporting and Timeline
Process………………………………………………………...32
15.2 Bleeding…………………………………………………………………………………...33-34
16. MONITORING……………………………………………………………………………….34
18. SITE CLOSURE………………………………………………………………...…...……….35
19. STUDY COMPLETION………………………………………………………..……………35
20. REGULATORY COMPLIANCE……………………………………………..……….……35
20.2 Institutional Review Board/Ethic Committee
Approvals……………………………………..36
20.3 Investigator Site
File…………………………………………………………..…………..36-37
21.0 PUBLICATION POLICY…………………………………………………………………..37
22.0 OTHER DEFINITIONS…………………………………………………………………37-39
01. CONTACTS AND HELPLINE
1st Floor, Batra Heart Centre
1 Tughlakabad, Institutional Area,
Email id:
[email protected]
Contact number: 011-29958747
Contract Research Organisation
6th Floor, Vatican Mindscapes
Email id
[email protected]
Contact Number 91-129-661-3500
criteria, endpoint events, and study flow.
TUXEDO-2 Clinical Helpline:
Contact 2: 91-9910990347 (Priyadarshini Arambam)
Contact 3: 91 – 8800799887 Dr Sonika Newar
The IWRS Technical Support Helpline is a service provided by the
JSS group to assist study
coordinators and investigators for technical support.
Contact: +91-9810991659
Leadership Committee
This is the primary decision-making body for the study and is
responsible for its successful
completion, including sustaining target enrolment and protocol
adherence. Members include the
Study Chair and Co- Chair and Principal Investigators. The
committee will meet whenever required
to review the progress of the trial.
The committee members are as following which are listed below:
-
Chair- Prof. (Dr.) Upendra Kaul, Chairman Batra Heart Centre and
Dean Academics and Research,
Batra Hospital & Medical Research Centre, New Delhi
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Co-Chair- Dr.Sripal Bangalore, Professor of Medicine,Director
Complex Coronary System,
Director of Research, Cardiac Catheterization laboratory, Director
Clinical Outcomes Group,The
Leon H.Charney Division of Cardiology,New York University School of
Medicine
Lead Principal Investigator- Prof. (Dr.) Upendra Kaul,Chairman
Batra Heart Centre and Dean
Academics and Research, Batra Hospital & Medical Research
Centre, New Delhi
Steering Committee
The functions of the steering committee are written in the
protocol.
The Steering committee members are as following which are listed
below: -
Prof. (Dr.) Upendra Kaul, Batra Hospital & Medical Research
Centre, New Delhi
Dr. Sripal Bangalore, New York University School of Medicine
Prof. Patrick W. Serruys, National Heart & Lung Institute
(NHLI) of Imperial College in London
Dr Ajit Mullasari, Madras Medical Mission, Chennai
Dr Dhiman Kahali, Birla Heart Institute, Kolkata
Dr Rajpal Abhaychand, GKNM Hospital, Coimbatore
Dr Praveen Chandra, Medanta The Medicity, Gurgaon
Dr Rishi Sethi, King George’s Medical University, Lucknow
Clinical Event Review Committee
The functions of the Clinical Event Review Committee are written in
the protocol and CEC
Charter.
Publications Committee
This committee reviews all proposals, drafts, and final versions of
research abstracts, presentations,
and manuscripts to be submitted to peer-reviewed journals and
national and international scientific
meetings. The functions and responsibilities of this committee is
written under Section 21 of the
Manual of Operations.
There will be a separate publication agreement which will be
circulated to the investigators before
the publication process.
2. Role of Academics and Research Dept. Batra Hospital and Medical
Research Centre.
As Sponsor, Academics and Research Department, Batra Hospital and
Medical Research Centre
has the overall responsibility for the conduct of the study,
including assurance that the study
satisfies international standards and the regulatory requirements
of the relevant competent
authorities.
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Prior to allowing the sites to start enrolling patients into the
study, the sponsor is responsible for
selecting investigators, ensuring EC/IRB approvals are obtained
where applicable, and signing the
Investigator Site Agreement with the investigators and/or
hospitals. It is the sponsor’s responsibility
to ensure that the study is conducted according to ISO 14155, the
Declaration of Helsinki, and other
applicable regulatory requirements, the study protocol, and any
conditions of approval imposed by
the EC/IRB or regulatory authorities. Additionally, the sponsor
will ensure proper clinical site
monitoring.
The sponsor will select qualified investigators and facilities
which have adequate study patient
population to meet the requirements of the investigation.
2.3 Training of investigator and site personnel and site
monitoring
The training of the investigator and appropriate clinical site
personnel will be the responsibility of
the sponsor and CRO, or designee, and may be conducted during an
investigator meeting, a site
initiation visit, or other appropriate training sessions. Periodic
monitoring visits will be conducted to
ensure that all clinical patient data are properly documented and
that the study is properly conducted.
2.4 Documentation
The Sponsor will collect, store, guard and ensure completion by the
relevant parties of the following
documents;
• All study relevant documents (protocol, Investigator’s Brochure,
EC/IRB approval and
comments, competent authority notification and comments, patient
information and
informed consent template, relevant correspondence, etc.)
• Signed and dated Case Report Form (eCRF)
• Records of any Serious Adverse Events (SAEs) reported to the
sponsor during the clinical
investigation
• Final report of the clinical investigation
2.5 Insurance
The sponsor will have insurance coverage for this study in
accordance with the laws and regulations
of India. Reimbursement, indemnity and insurance shall be addressed
in a separate agreement on
terms agreed upon by the parties.
2.6 Supplemental Applications
As appropriate, the CRO on behalf of the sponsor will submit
changes to the study protocol to the
investigators to obtain EC/IRB re-approval.
2.7 Submitting Reports
The sponsor or its designee will submit the appropriate reports
identified by the regulations. This
includes withdrawal of any EC/IRB approval, interim (if any) and
final reports.
2.8 Maintaining Records
The Sponsor will maintain copies of correspondence, data, SAEs and
other records related to the
clinical study. The Sponsor will maintain records related to the
signed Investigator Site Agreements
according to requirements set forth by ISO 14155.CRO and clinical
sites will maintain study records
according to local requirements for this type of study.
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2.9 Audit
The sponsor or its designee is responsible for auditing the study
to ensure compliance with GCP and
regulatory requirements. A member of the sponsor or a designated
CRO’s quality assurance unit may
arrange to conduct an on-site audit to assess the performance of
the study at the study site and of the
study documents originating there.
2.10 Confidentiality
All data and information collected during this study related to the
participating subject will comply
with the standards for protection of privacy based on applicable
local/ national requirements for
subject’s confidentiality. All data used in the analysis and
summary of this study will be anonymous,
and without reference to specific study subjects’ names. Access to
study subject files will be limited
to authorized personnel of the Sponsor, the investigator, and
research staff. Authorized regulatory
personnel have the right to inspect and copy all records pertinent
to this study, but all efforts must
be made to remove the subject’s personal data.
03. SITE START-UP REQUIREMENTS
03.1 OVERVIEW OF SITE ACTIVATION REQUIREMENT
Before a site can be approved to start enrolment, several ethical,
contract, and administrative
requirements must be completed. Site approval requirements are
listed below. Requested
documentation should be submitted to the CRO electronically to
[email protected]
and original copies of all forms should be kept at the site and a
copy sent to the sponsor and CRO.
When all the requirements for site initiation are satisfied, you
will be completed and notified that
your site may begin participant in enrolment.
Required Documents
• Approved Informed Consent Form
• Protocol Signature page signed and dated by the Principal
Investigator (PI)
• Recent (≤ 1 year old) signed and dated English Curriculum Vitae
(CVs) of the Principal
Investigator and co-investigators of the clinical site. These CVs
should clearly show the
investigator’s and co-investigators’ qualifications and
experiences.
• Valid Medical registration certificate attested by the
investigator himself/herself.
• Copy of the written confirmation of the EC/IRB regarding approval
of the protocol including
version number and date, patient information sheet and informed
consent form, including
version and date and other adjunctive patient materials.
• Listing of any conditions attached to the approval
• List of EC/IRB members, including name, title, occupation and any
institutional affiliation
of each member.
• Signed Investigator Site Agreement.
• Any other relevant documents which need EC/ IRB approval
• Lab reference ranges.
03.2.1 PROTOCOL-SPECIFIC TRAINING
Principal Investigators and study coordinators will be trained on
the protocol prior to enrolment of
participants by the CRO or sponsor representative. In general,
initial training for investigators and
study coordinators will be done in person but may also be done
remotely. Investigators and study
coordinators will be trained remotely via webinars, slides, video,
or by referring to relevant sections
of the protocol and/or the Manual of Operations. Training will
include an overview of the protocol
and all procedures, including completion of case report forms (for
study coordinators only). Principal
Investigators, study coordinators should complete additional
recommended training for any protocol
amendment.
The Principal Investigator will attest to his/her agreement to
adhere to the protocol by completing a
signed Protocol Signature Page. Other site personnel completing
protocol training remotely will be
required to sign training form to confirm that required training
modules were completed and
understood, and that any questions were addressed as needed by the
CRO or sponsor team.
03.2.2 ICH GCP TRAINING
The Principal Investigator and study coordinator(s) at each site
are also required to have completed
ICH GCP training prior to participating in study -related
activities. All the site staffs should be
trained on the latest guidelines of GCP and other required
regulatory requirements.
03.3 NEW SITE PERSONNEL
When new site personnel are assigned to support activities for the
TUXEDO-2 study, it should be
notified to the CRO. New site personnel must complete all required
training. Protocol training will
be coordinated by the sponsor or CRO representative. A training
form must be signed to attest that
required training modules were completed and understood, and that
any questions were addressed as
needed by the sponsor and CRO. The delegation log should be updated
and signed and shared with
the CRO.
AMENDMENTS
Before a site can be approved to start enrolment under a protocol
amendment, the same requirements
as mentioned in section 03.1 must be completed.
In case of minor amendments in the protocol or any study documents,
only EC notification should
be sufficient while in case of major amendments the EC approval is
required.
04. RECRUITMENT, SCREENING AND RANDOMIZATION
04.1 Screening process
Participants will be identified from cardiac OPDs and from cardiac
wards who are admitted for
angiography. Once angiography confirms the eligibility of the
patient to undergo PCI, they will be
screened for their eligibility for participation in the
study.
If a patient has done coronary angiography (CAG) from other
institute but willing to undergo
angioplasty in the study institute, that patient can also be
considered eligible for screening.
04.2 Screening log
Screening logs will be provided by the CRO to all the active sites.
All participants screened for
TUXEDO-2 study, irrespective of their eligibility for randomization
will be entered in this log
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04.1. PARTICIPANT INCLUSION/EXCLUSION CRITERIA
For detailed information of the Inclusion criteria refer to
protocol.
Following are few inclusion criteria which have been elaborated for
better understanding -
• Patient with diabetes mellitus (Type 1 or Type 2)
Any patient on drug treatment for diabetes will be eligible for
recruiting in the study. Patient
diagnosed for the first time will be selected based on the
following criteria -
Criteria for diagnosis for diabetes will follow the chart for the
American Diabetes Association
Diabetes Care Jan 2019
FPG ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric
intake for at least 8 hrs. before the
test OR
A1C ≥6.5% (48 mmol/mol). OR
In a patient with classic symptoms of hyperglycaemia or
hyperglycaemic crisis, a random plasma
glucose ≥200 mg/dL (11.1 mmol/L).
• Angina/angina equivalents and/or objective evidence of myocardial
ischemia will be
assessed using the Braun Wald’s and CCS classification of
angina
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ANGINA PECTORIS
Severity
extracardiac condition
(primary UA)
acute myocardial infarction
accelerated angina; no rest pain IA IB IC
II
rest, subacute)
rest, acute) IIIA
24 h, % 30 Days, % 6 mo, %
Tpos 5 15-20 25
Tneg <1 <2 <5
Canadian Cardiovascular Society (CCS) Classification of Stable
Angina:
CLASS
• Walking 1-2 level blocks at a normal pace
• Climbing 1 flight of stairs at a normal pace
IV Angina at any level of physical exertion****
1. *Ordinary physical activity does not cause angina; for example,
walking or climbing stairs, angina occurs with strenuous or rapid
or
prolonged exertion at work or recreation.
2. ** Slight limitation of ordinary activity; for example, angina
occurs walking or stair climbing rapidly, walking uphill, walking
or stair
climbing after meals or in cold, in wind or under emotional stress
or only during the few hours after awakening. Walking more than
two
blocks on the level and climbing more than one flight of ordinary
stairs at a normal pace and in normal conditions.
3. ***Marked limitation of ordinary activity; for example, angina
occurs walking one or two blocks on the level and climbing one
flight of
stairs in normal conditions and at a normal pace.
4. **** Inability to carry on any physical activity without
discomfort - angina syndrome may be present at rest.
Objective evidence of myocardial ischemia is assessed by stress
ECG, stress ECHO and stress Thallium
04.1.2 Exclusion Criteria
For detailed information of the Exclusion criteria refer to
protocol.
Following are few exclusion criteria which have been elaborated for
better understanding -
• Severe congestive heart failure (class III or IV according to
NYHA, or pulmonary edema) at the time of enrolment will not be
included.
NYHA will be assesses using NYHA classification
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CHF (CONGESTIVE HEART FAILURE)
NYHA (New York Heart Association) Classification - The Stages of
Heart Failure
1 Class I No symptoms and no limitation in ordinary physical
activity, e.g. shortness of breath when walking, climbing stairs
etc.,
2 Class II Mild symptoms (mild shortness of breath and/or angina)
and slight limitation during ordinary activity
3 Class III
Marked limitation in activity due to symptoms, even during
less-than-ordinary activity, e.g. walking short distances
(20—100
m). Comfortable only at rest.
4 Class IV Severe limitations. Experiences symptoms even while at
rest. Mostly bedbound patients
5 ____ No NYHA class listed or unable to determine
Previous stroke within 6 months or patients with stroke at more
than 6 months with significant residual neurologic involvement, as
reflected in
a Rankin Score > 1.
Rankin score will be assessed by using the below Scale.
Modified Rankin scale (MRS) (Stroke; Broderick et al 2017: 48; 2007
-2012)
0 No symptoms
1 No significant disability. Able to carry out all usual activities
despite symptoms
2 Slight disability. Able to look after own affairs without
assistance, but unable to carry out all previous activities
3 Moderate disability. Requires some help, but able to walk
unassisted.
4 Moderately severe disability. Unable to attend to own bodily
needs without assistance, and unable to walk unassisted.
5 Severe disability. Requires constant nursing care and attention,
bedridden, incontinent.
6 Dead
04.2. CRITERIA FOR ENROLLMENT (INFORMED CONSENT) AND PRIOR TO
RANDOMIZATION
04.2.1 Informed consent
Patients who provide informed consent and are clinically eligible
to participate will be enrolled via the
IWRS system and will receive an ID number.
The sponsor will provide model informed consent documents to the
clinical sites. Use of these template
documents—with limited, locally required revision only—is strongly
encouraged. Sites need to submit
to their Institutional Review Board (IRB)/ Ethics Committee (EC),
only the documents they will be
using. Participant enrolment cannot begin until the local
IRB/REB/EC has approved the TUXEDO-2
protocol and all applicable consent documents.
Informed consent must be obtained at the first TUXEDO-2 visit.
Principles of informed consent, as
detailed in the International Conference on Harmonisation Good
Clinical Practice guideline, any local
institutional policies, and any local, state, and country
regulatory requirements must be adhered to
Consenting will be performed by the investigator or designee who is
well versed in the protocol and is
able to answer questions about the study, including procedures,
risks, and alternatives. Non-technical
and easily understood language should be used.
04.2.2 Vernacular language
All informed consent documents will be translated to the vernacular
language as per the site
requirement. Translation certificates and back translated documents
will be provided by the CRO which
should be submitted to ethics committee for review and
approval.
04.2.3 Informed consent process:
Written informed consent will be obtained from all participants or
his/her legally acceptable
representative. Audio-visual recording of consent process is not
applicable for this study since it
involves neither a new chemical entity nor new molecular
entity.
In case participant was admitted in emergency and study team do not
have enough time to obtain consent
from the participant, consent may be obtained from his/her legally
acceptable representative on his/her
behalf. Once the participant is stable, he/she can provide consent
by signing on the informed consent
document in the presence of the investigator or his/her designee.
The same should be documented and
kept in the participant’s file.
In case the participant or his/her legally acceptable
representative is unable to read and write, a thumb
impression from the participant/legally acceptable representative
should be obtained and an impartial
witness should be present during the entire consent process who
will append his/her signature on the
informed consent form.
04.2.4 SCHEDULE OF ASSESSMENTS
weight, blood pressure, heart rate)a × × × × × ×
Medical history including DM ×
HbA1ce × × ×
CBC × × ×
Safety assessments (UADE, SAE and SADE
assessment, health status information,
Vital status confirmation × × ×
a. Height is only required at screening visit. Physical
examinations and vital signs assessments only required if visit is
completed in clinic
b. LVEF as evaluated by angiography, echocardiogram or radionuclide
ventriculography within 30 days prior to enrollment can also be
considered for
screening
c, d. ECG should be done within ≤ 24 hrs. pre-procedure and within
≤ 24 hrs. post-procedure
e. 1 month and 24-month visits may be conducted via telephone,
email or clinic visit depending upon the participant stability and
geography. If patient
cannot come for clinic visit, patient should be counselled to do an
ECG and share it with the site.
Laboratory tests (HbA1c, electrolytes, Serum creatinine and lipid
profile) if done prior to 14 days of screening, reports will be
considered. If done as
part of standard of care, the reports will be considered and
patients do not need to undergo these tests again.
f. Troponin test to be done in case CK/CKMB is not done at
site
* Troponin/CK/ CKMB to be done at ≤ 24 hrs. pre procedure, 8-hrs
post procedure to be repeated. In case of cardiac enzymes elevation
(CK > 2 times
ULN or CKMB > 3 times ULN or cTn/hs-cTn > 35 ULN) at least 2
samples (within preferred interval of 6 hours) should be obtained
prior to discharge.
g. Randomization should occur within 78 hours after obtaining
informed consent
h. UADE, SAE, SADE assessment will be done at each follow-up visit
till 2 year. Health status information, hospitalization
information, repeat-
revascularization information will be collected at 3, 4 and 5
years.
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04.3 SCREENING TO RANDOMIZATION VISITS
A patient may be randomized when written informed consent is
obtained and eligibility has been
confirmed. The screening and randomization visit procedures can be
done at the same visit.
The target for randomization of eligible participants is within 72
hrs. of informed consent. If 72 hrs.
are exceeded, contact the CRO representative for instructions on
how to proceed.
In case of staged procedure, the timeline for randomization will
not be applicable. The same arm of
stent which was assigned through IWRS during the initial
randomization will be applicable for the
staged procedure.
Note: - If the patient gets angiography imaging test done from
outside it can be considered.
Assessments to be done at screening till randomization:
• Informed consent
• Medical history
• Angina assessment
• 2-D Echocardiogram
• 12-lead electrocardiogram
• Laboratory assessments (HbA1c, lipid profile, s. creatinine,
electrolytes, cardiac enzymes,
CBC) (* eGFR calculation should be done using the URL eGFR
Calculator - UKidney's
Nephrology Community
URL: http://www.syntaxscore.com/calculator/start.htm
4.3.1 ANGINA STATUS (Coronary Artery Disease presentation)
STEMI: ST-Elevation Myocardial Infarction (STEMI) is a very serious
type of heart attack during
which one of the heart's major arteries (one of the arteries that
supplies oxygen and nutrient-rich blood
to the heart muscle) is blocked. ST-segment elevation is an
abnormality detected on the 12-lead ECG.
An acute ST-elevation myocardial infarction (STEMI) is an event in
which transmural myocardial
ischemia results in myocardial injury or necrosis. It also required
confirmation of the myocardial
ischemic injury with abnormal cardiac biomarkers.
NSTEMI: Non-ST-elevation myocardial infarction (NSTEMI) is an acute
ischemic event causing
myocyte necrosis. The initial ECG may show ischemic changes such as
ST depressions, T-wave
inversions, or transient ST elevations; however, it may also be
normal or show nonspecific changes.
NSTEMI encompasses a broad spectrum of ischemic injury to the
myocardium, which is detected by
elevation of troponin. It can be distinguished from unstable angina
pectoris by normal serial troponin.
Unstable Angina: Unstable angina (UA) is an acute coronary syndrome
that is defined by the absence
of biochemical evidence of myocardial damage. It is characterized
by specific clinical findings of
prolonged (>20 minutes) angina at rest; new onset of severe
angina; angina that is increasing in
frequency, longer in duration, or lower in threshold; or angina
that occurs after a recent episode of
myocardial infarction.
TUXEDO-2-INDIA Page 18 of 40
Stable Angina: Stable angina is a sensation of discomfort or pain
in the chest, arm, or jaw brought on
predictably by factors that increase myocardial oxygen demand, such
as exertion, and relieved by rest.
Silent Ischemia: Silent myocardial ischemia is defined as objective
documentation of myocardial
ischemia in the absence of angina or anginal equivalents.
Angina Equivalent: Anginal equivalents are those symptoms such as
dyspnoea, faintness,
fatigue, diaphoresis, nausea and emesis, lightheadedness, and
eructations in absence of chest pain.
04.3.2 Randomization:
Please refer to the IWRS operation manual for detail randomization
procedures.
04.3.3 STUDY FLOW
05.1 INVASIVE PROCEDURES
Screening
Meet all the inclusion and none of the exclusion criteria and
determine criteria
for PCI
1-Month±7 days (Clinic/Telephonic), 6-Month±30 days (Clinic),
12-Month ±30 days(Clinic), 24-Month
±30 days(Clinic/Telephonic), 36-Month±30 days (Telephonic),
48-Month±30 days (Telephonic), 60-
Month±30 days (Telephonic)
disease
05. INVASIVE PROCEDURES, CARDIAC MARKERS & POSTPROCEDURE
ECGS
05.1 INVASIVE PROCEDURES
In this study we are going to use two stents - Supraflex Cruz and
Xience family stents.
The XIENCE group control device matrix for the Tuxedo 2- India is
shown below.
Available stents diameter (mm) Available stents length (mm)
XIENCE V 2.5, 2.75, 3.0, 3.5, 4.0 8, 12, 15, 18, 23, 28
XIENCE PRIME 2.25, 2.5, 2.75, 3.0, 3.5, 4.0 8, 12, 15,18, 23
XIENCE PRIME LL 2.25*, 2.5, 2.75, 3.0, 3.5, 4.0 8, 12, 15,18,
23
XIENCE Xpedition SV 2.25*, 2.5, 2.75, 3.0, 3.5, 4.0 8, 12, 15, 18,
23, 28
XIENCE Xpedition 2.5, 2.75, 3.0, 3.25, 3.5, 4.0 8, 12, 15, 18, 23,
28
XIENCE Xpedition LL 2.5, 2.75, 3.0, 3.25, 3.5, 4.0 33 and 38
* The 2.25 mm stent diameter for XIENCE PRIME LL is only available
in the 28 mm stent length.
The Supraflex Crux device matrix is shown below
Length (mm)
8.0 12.0 16.0 20.0 24.0 28.0 32.0 36.0 40.0 44.0 48.0
D ia
m et
05.2 CARDIAC MARKERS (TROPONIN AND CK-MB)
Staged Procedures: If the participant has a staged procedure the
cardiac markers must be obtained
before (on the date of the procedure) and after EACH
procedure.
Pre-Procedure Collection (for all procedures): Troponin/CK/ CKMB to
be done at ≤ 24 hrs. pre
procedure.
Post-Procedure Collection: 8-hrs post procedure to be repeated. In
case of cardiac enzymes elevation
(CK > 2 times ULN or CKMB > 3 times ULN or cTn/hs-cTn > 35
ULN) at least 2 samples (within
preferred interval of 6 hours) should be obtained prior to
discharge.
05.3 PRE AND POST-PROCEDURE ECGS
ECG should be done within ≤ 24 hrs. pre-procedure and within ≤ 24
hrs. post-procedure. For staged
procedure, pre and post ECG for each procedure should be done
TUXEDO-2-INDIA Page 21 of 40
06. SCREEN FAILURES
To be considered an enrolled participant, one must meet all
clinical eligibility criteria, had screening
visit, signed consent to participate in the study, and be enrolled
through IWRS and assigned a study
number.
Screen failures refer to patients ineligible to participate in the
study
07. IWRS
08. ENDPOINTS:
• For stroke, complete the Stroke form.
• For MI, complete the Myocardial Infarction form.
• For Stent Thrombosis, complete the Stent Thrombosis form.
• For PCI or CABG, complete the revascularization or CABG
form.
REVASCULARISATION: restoration of blood supply to the heart by
means of coronary angioplasty
(PCI) or bypass surgery (CABG)
Target Lesion Failure (TLF)
Target lesion failure is any ischemia-driven revascularisation of
the target lesion, MI (Q-wave and non-
Q-wave) related to the target vessel, or (cardiac) death related to
the target vessel. For the purposes of
this protocol, if it cannot be determined with certainty whether
the MI or death was related to the target
vessel, it will be considered a TLF.
ID -Target Lesion Revascularization (TLR)
Ischemia-driven TLR is defined as any repeat percutaneous
intervention of the target lesion or bypass
surgery of the target vessel performed for restenosis or other
complication of the target lesion. All TLR
should be classified prospectively as clinically indicated [CI] or
not clinically indicated by the
investigator prior to repeat angiography. The target lesion is
defined as the treated segment from 5 mm
proximal to the stent and to 5 mm distal to the stent.
ID -Target Vessel Revascularization (TVR)
Ischemia-driven TVR is defined as any repeat percutaneous
intervention or surgical bypass of any
segment of the target vessel. The target vessel is defined as the
entire major coronary vessel proximal
and distal to the target lesion which includes upstream and
downstream branches and the target lesion
itself
Target vessel failure is any ischemia-driven revascularisation of
the target vessel, MI (Q-wave and non-
Q-Wave) related to the target vessel or death related to the target
vessel. For the purposes of this
protocol, if it cannot be determined with certainty whether the MI
or death was related to the target
vessel, it will be considered a TVF.
TUXEDO-2-INDIA Page 22 of 40
Target Vessel Myocardial Infarction (TV MI)
Myocardial Infarction not clearly attributable to a non –target
vessel
Note: TLR and TVR will be adjudicated by the Clinical Event
Committee.
ID -Target Lesion Revascularization (ID-TLR/TVR)
A revascularization is considered clinically indicated if
associated with any of the following:
o Positive functional ischemia study including positive FFR
o Ischemic symptoms and angiographic diameter stenosis ≥50% by core
laboratory QCA
Angiographic diameter stenosis ≥70% by core laboratory QCA without
angina or positive
functional study
All-cause mortality
Nonfatal MI:
MYOCARDIAL INFARCTION (MI)
Myocardial infarction according to Fourth Universal definition
(2018)
Universal definitions of myocardial injury and myocardial
infarction
Criteria for myocardial injury
The term myocardial injury should be used when there is evidence of
elevated cardiac troponin
values (cTn) with at least one value above the 99th percentile
upper reference limit (URL). The
myocardial injury is considered acute if there is a rise and/or
fall of cTn values
Criteria for acute myocardial infarction (types 1, 2 and 3
MI)
The term acute myocardial infarction should be used when there is
acute myocardial injury with
clinical evidence of acute myocardial ischaemia and with detection
of a rise and/or fall of cTn values
with at least one value above the 99th percentile URL and at least
one of the following:
-Symptoms of myocardial ischaemia;
-New ischaemic ECG changes;
-Development of pathological Q waves;
-Imaging evidence of new loss of viable myocardium or new regional
wall motion abnormality in a
pattern consistent with an ischaemic aetiology;
-Identification of a coronary thrombus by angiography or autopsy
(not for type 2 or 3 MIs).
Post-mortem demonstration of acute athero-thrombosis in the artery
supplying the infarcted
myocardium meets criteria for type 1 MI.
Evidence of an imbalance between myocardial oxygen supply and
demand unrelated to acute athero-
thrombosis meets criteria for type 2 MI.
Cardiac death in patients with symptoms suggestive of myocardial
ischaemia and presumed new
ischaemic ECG changes before cTn values become available or
abnormal meets criteria for type 3
MI.
Criteria for coronary procedure-related myocardial infarction
(types 4 and 5 MI)
Percutaneous coronary intervention (PCI) related MI is termed type
4a MI.
Coronary artery bypass grafting (CABG) related MI is termed type 5
MI.
Coronary procedure-related MI ≤ 48 hours after the index procedure
is arbitrarily defined by an
elevation of cTn values > 5 times for type 4a MI and > 10
times for type 5 MI of the 99th percentile
URL in patients with normal baseline values. Patients with elevated
pre-procedural cTn values, in
whom the pre-procedural cTn level are stable ( ≤20% variation) or
falling, must meet the criteria for
TUXEDO-2-INDIA Page 23 of 40
a > 5 or > 10-fold increase and manifest a change from the
baseline value of > 20%. In addition,
with at least one of the following:
- New ischaemic ECG changes (this criterion is related to type 4a
MI only);
- Development of new pathological Q waves;
- Imaging evidence of loss of viable myocardium that is presumed to
be new and, in a pattern,
consistent with an ischaemic aetiology;
- Angiographic findings consistent with a procedural flow-limiting
complication such as coronary
dissection, occlusion of a major epicardial artery or graft,
side-branch occlusion-thrombus,
disruption of collateral flow or distal embolization.
Isolated development of new pathological Q waves meets the type 4a
MI or type 5 MI criteria with
either revascularization procedure if cTn values are elevated and
rising but less than the pre-
specified thresholds for PCI and CABG.
Other types of 4 MI include type 4b MI stent thrombosis and type 4c
MI restenosis that both meet
type 1 MI criteria.
Post-mortem demonstration of a procedure-related thrombus meets the
type 4a MI criteria or type
4b MI criteria if associated with a stent.
Criteria for prior or silent/unrecognized myocardial
infarction
Any one of the following criteria meets the diagnosis for prior or
silent/ unrecognized MI:
- Abnormal Q waves with or without symptoms in the absence of
non-ischaemic causes.
- Imaging evidence of loss of viable myocardium in a pattern
consistent with ischaemic aetiology.
- Patho-anatomical findings of a prior MI.
PERI-PROCEDURAL MYOCARDIAL INFARCTION (SCAI 2013)
Q wave MI: (QMI) will require one of the following criteria:
Peri-procedural MI after PCI or CABG (<48 hours post- PCI or
CABG)
For patients with normal baseline cardiac biomarkers: any of the
following criteria:
CK-MB ≥10×ULN or cTn (I or T) ≥70×ULN
OR: CK-MB ≥ 5×ULN or cTn (I or T) ≥35×ULN may be accepted in
combination with any
of the following:
- OR: new persistent LBBB
For patients with elevated baseline cardiac biomarkers: any of the
following criteria:
When biomarker levels are stable or falling, there should be new
CK-MB elevation by an
absolute increment of ≥10×ULN (or ≥70×ULN for cTnI or T) from the
previous nadir level
When biomarker levels have not been shown to be stable or falling,
there should be a further
rise in CK-MB or troponin beyond the most recently measured value
by an absolute increment
of ≥10×ULN in CK-MB or ≥70×ULN in cTn plus new ST-segment elevation
or depression
plus signs consistent with a clinically relevant MI, such as new
onset or worsening heart
failure or sustained hypotension.
While not currently recommended as part of this definition, use of
post-CABG ECGs, indices of
hemodynamic instability, and imaging studies demonstrating new wall
motion abnormalities are
suggested to complement biomarker elevations post- CABG to improve
specificity.
TUXEDO-2-INDIA Page 24 of 40
• Chest pain or other acute symptoms consistent with myocardial
ischemia and new
pathological Q waves in two or more contiguous ECG leads as
determined by the CEC,
in the absence of timely cardiac enzyme data.
• New pathologic Q waves in two or more contiguous ECG leads as
determined by CEC
and elevation of cardiac enzymes. In the absence of ECG data the
CEC may adjudicate
Q wave MI based on the clinical scenario and appropriate cardiac
enzyme data.
MACE
A composite of all-cause mortality, nonfatal myocardial infarction
(MI), or stroke
DEATH (ARC Circulation 2007; 115: 2344-2351)
The deaths will be adjudicated per the ARC definition. All deaths
are considered cardiac unless an
unequivocal non-cardiac cause can be established. Specifically, any
unexpected death even in patients
with coexisting potentially fatal non-cardiac disease (e.g. cancer,
infection) should be classified as
cardiac.
Cardiac death:
Any death due to proximate cardiac cause (e.g. MI, low-output
failure, fatal arrhythmia),
unwitnessed death and death of unknown cause, all study procedure
related deaths including those
related to concomitant treatment.
Death due to non-coronary vascular causes such as cerebrovascular
disease, pulmonary
embolism, ruptured aortic aneurysm, dissecting aneurysm, or other
vascular cause.
Non-cardiovascular death:
Any death not covered by the above definitions such as death caused
by infection, malignancy,
sepsis, pulmonary causes, accident, suicide or trauma.
STROKE
[Cerebrovascular Accident (CVA) / Stroke]
Stroke is defined as a sudden onset of focal neurological deficits
due to vascular lesions of the brain that
persists >24 hours. Any neurological symptom that lasts < 24
hours is classified as transient ischemic
attack (TIA). Stroke results from either of two types of cerebral
vascular disturbance: ischemia or
haemorrhage.
*National Institute of Health Stroke Scale must be used for
quantifying the severity of stroke.
Ischemic Stroke: American Stroke Association
https://www.stroke.org/en/about-stroke/types-of-
stroke/ischemic-stroke-clots
Ischemic stroke occurs when a vessel supplying blood to the brain
is obstructed. It accounts for about
87 percent of all strokes.
Hemorrhagic Stroke: American Stroke Association
https://www.stroke.org/en/about-stroke/types-
of-stroke/hemorrhagic-strokes-bleeds
It’s caused by a weakened vessel that ruptures and bleeds into the
surrounding brain. The blood
accumulates and compresses the surrounding brain tissue
[Transient ischemic attack (TIA)]
TIAs are focal neurologic abnormalities of sudden onset and brief
duration (i.e., lasting less than 24
hours) that reflect dysfunction in the distribution of the affected
artery. TIAs include transient
monocular blindness (e.g., amaurosis fugax defined as a transient
episode of monocular blindness, or
partial blindness, lasting ten minutes or less) and transient
hemispheric attacks.
STENT THROMBOSIS (ARC Circulation 2007; 115: 2344-2351)
Stent thrombosis should be reported as a cumulative value at the
different time points and with the
different separate time points. Time 0 is defined as the time point
after the guiding catheter has been
removed and the subject left the catheterization lab.
Timing:
Subacute stent thrombosis*: >24 hours - 30 days post stent
implantation
Late stent thrombosis†: 30 days - 1-year post stent
implantation
Very late stent/ thrombosis†: >1-year post stent
implantation
*Acute/subacute can also be replaced by early stent
thrombosis.Early stent thrombosis (0 - 30 days) -
this definition is currently used in the community.
†Including “primary” as well as “secondary” late stent thrombosis;
“secondary” late stent thrombosis is
a stent thrombosis after a target segment revascularization.
Categories:
Definite stent thrombosis
Definite stent thrombosis is considered to have occurred by either
angiographic or pathologic
confirmation.
Angiographic confirmation of stent thrombosis*
The presence of a thrombus† that originates in the stent or in the
segment 5 mm proximal or distal to
the stent and presence of at least one of the following criteria
within a 48-hour time window:
o Acute onset of ischemic symptoms at rest
o New ischemic ECG changes that suggest acute ischemia
o Typical elevation or depression in cardiac biomarkers (refer to
definition of spontaneous MI)
o Nonocclusive thrombosis
• Thrombus Intracoronary thrombus is defined as a (spheric, ovoid,
or irregular)
noncalcified filling defect or lucency surrounded by contrast
material (on 3 sides or
within a coronary stenosis) seen in multiple projections, or
persistence of contrast
material within the lumen, or a visible embolization of
intraluminal material
downstream.
o Occlusive thrombus
o TIMI 0 or TIMI 1 in-stent or proximal to a stent up to the most
adjacent proximal side branch or
main branch (if originates from the side branch).
* The incidental angiographic documentation of stent occlusion in
the absence of clinical signs or
symptoms is not considered a confirmed stent thrombosis.
† Intracoronary thrombus.
TUXEDO-2-INDIA Page 26 of 40
Pathological confirmation of stent thrombosis
Evidence of recent thrombus within the stent determined at autopsy
or via examination of tissue
retrieved following thrombectomy.
Probable stent thrombosis
Either of the following occurred after stent implantation will be
considered a probable stent thrombosis:
o Any unexplained death within the first 30 days‡
o Irrespective of the time after the index procedure, any MI* that
is related to documented acute
ischemia in the territory of the implanted stent without
angiographic confirmation of stent
thrombosis and in the absence of any other obvious cause
‡ For studies with ST-elevation MI population, one may consider the
exclusion of unexplained death
within 30 days as evidence of probable stent thrombosis.
*SCAI consensus for peri-procedure MI ≤48 hours, and 3rd universal
definition for MI>48 hours after
index procedure.
Possible stent thrombosis
Clinical definition of possible stent thrombosis is considered to
have occurred with any unexplained
death from 30 days following intracoronary stenting until end of
trial follow up.
08.1 Procedural Endpoints
Device Success: An attainment of visually estimated, residual
stenosis of < 30% of the target
lesion
Lesion Success: An attainment of < 30% residual stenosis using
any device during the
procedure
Procedural Success: An attainment of lesion success without the
occurrence of in hospital
MACE
Procedural Complication Rate: This would include complete and
individual angiographic
occurrence of a dissection > Type B, no re-flow, distal
embolization, perforation or abrupt
closure
DISSECTION
National Heart, Lung, and Blood Institute [NHLBI] Dissection
Classification System is used.
A. Minor radiolucencies within the lumen during contrast injection
with no persistence after dye
clearance.
B. Parallel tracts or double lumen separated by a radiolucent area
during contrast injection with no
persistence after dye clearance.
C. Extraluminal cap with persistence of contrast after dye
clearance from the lumen.
D. Spiral luminal filling defects.
E. New persistent filling defects.
F. Non-A-E types that lead to impaired flow or total occlusion.
Note: Type E and F dissections
may represent thrombus.
09. FOLLOW-UP SCHEDULE
1. Following the randomization visit, the study coordinator will
follow-up with each participant at
1 month, 6 months, 12 months, 24 months, 36 months, 48 months and
60 months.
2. If an in-person visit is not performed, it is still possible to
collect information for the electronic
case report form (eCRF) such as smoking status, physical activity,
self-reported blood pressure
and weight, or data from personal physician records that include
blood pressure, weight, and
lipid results.
3. At every clinic visit, review New York Heart Association (NYHA)
heart failure classification,
Canadian Cardiovascular Society (CCS) and angina
classification.
4. The study coordinator will also record the death of any
participant during course of the trial.
5. Other forms of contact should be used, such as telephone;
e-mail; communication with a
personal physician, other allied health professional, or family
member; or review of electronic
health record or public records, to ensure participant
follow-up.
10. TIMELINE AND VISIT SCHEDULE
All enrolled patients will be followed up at 1, 6, 12, 24, 36, 48
and 60 months.
1(±7 days) month/24 month (±30 days)
• Angina assessment
• 12-lead electrocardiogram
• Current Cardiac and Diabetic medications
• Safety assessment
• Laboratory assessments (HbA1c, lipid profile, electrolytes (Na,
K, Cl), CBC)
• Current Cardiac and Diabetic medications
• Safety assessment
• Laboratory assessments (HbA1c, lipid profile, S.creatinine and
electrolytes (Na, K, Cl), CBC)
• Current Cardiac and Diabetic medications
• Safety assessment
36 months (±30 days)/48 month (±30 days)/60 month (±30 days)
• Angina assessment
11.1.1 Appointment Hours: Study participants should be considered
"customers." As volunteers, they
should be a priority in booking visits at convenient time slots.
The hours that staff is available for
TUXEDO-2 visits should be as flexible as possible to accommodate
participants' schedules.
11.1.2 Availability Outside Business Hours: Participants should be
able to talk with staff at times
other than study visits. This includes evenings and weekends.
11.1.3 Staff Willingness to Spend Time With Participants: The
perception that the staff is willing to
make extra efforts to accommodate participants’ needs enhances
retention. This begins at the front door
with friendly reception by staff and continues through the duration
of volunteers’ participation in
TUXEDO-2. Pleasant, kind, helpful, and attentive staff will
facilitate bonding and retention.
11.1.4 Facilitating Appointments:
There are a number of strategies that sites should follow to
facilitate participants keep appointments,
including:
1. Recording the next scheduled visit on the OPD/ consultation
card, which includes the center’s
telephone number and “check-off” statements to help participants
prepare for the next visit.
2. Mailing written reminders or placing telephone calls to the
participants a week before the
appointment.
12.1 OVERALL RETENTION
It is better to maintain contact with participants, even infrequent
contact, than to have them withdraw
completely from the trial. If a participant voices hesitation about
continuing in the trial, it is important
for site staff to talk about why they do not want to continue in
TUXEDO-2 and work with participant
to address their concerns. Engaging participants in topics
unrelated to TUXEDO-2 can also help
maintain contact. Maintaining even minimal contact with
participants during periods when motivation
is low makes it easier to re-engage them in the study.
12.2 PARTICIPANTS UNABLE-TO-CONTACT, LOST-TO-FOLLOW-UP, AND
WITHDRAWALS
12.2.1 UNABLE TO CONTACT
If unable to contact a participant, every means possible should be
made to locate and contact the
participant including but not limited to:
Sending email and mobile text messages
Contacting spouses or alternate contacts listed on the Participant
Information Form
Contacting emergency contacts identified on admissions.
Review electronic health records to determine vital status
Mailing a registered, return-receipt letter to the participant
requesting that they contact the study
team.
Visiting participants at their homes in case they reside within the
city or area where the study
centre is.
12.2.2 LOST-TO-FOLLOWUP
If vital status of the participant is known at the last study
visit, the participant will not be considered lost
to follow up. Continuous efforts should be made to contact the
participant till the end of the study.
TUXEDO-2-INDIA Page 29 of 40
12.2.3 WITHDRAWALS
Complete and accurate follow-up is extremely important for the
duration of the study. The participant,
however, may decline to continue protocol related assessments at
any time however every attempt will
be made to continue contact by telephone, written communication,
email, by proxy contact with family
and friends or allied healthcare providers. This does not
constitute withdrawal from the study. The
reason for withdrawal will be documented for all participants
withdrawn from the study.
13. TREATMENT STRATEGIES
13.1.1 Overview of Optimal Medical Therapy
• Risk factor control (BMI<27; systolic BP <130mm Hg; LDL
<50 mg/dl; Hba1c<7)
• Antiplatelet
• PCSK-9 inhibitors whenever indicated
All patients with stable coronary artery disease pre-index
procedure must receive dual anti-platelet
therapy, being aspirin (ASA) and platelet aggregation inhibition
therapy for at least 6 months after PCI
followed by ASA monotherapy indefinitely.
13.1.2.1 Randomization of antiplatelets therapy
All patients with acute coronary syndrome pre-index procedure must
receive dual anti- platelet therapy,
being aspirin (ASA) and platelet aggregation inhibition therapy for
at least 12 months after PCI followed
by ASA monotherapy indefinitely. IWRS will randomly allocate
prescribed DAPT in 1:1 manner across
subjects.
13.1.3 Angina Management
The goal is control of angina to optimize participants ‘quality of
life. Classification by the site
investigators according to the Canadian Cardiovascular Society
classification system.
13.1.4 Hypertension Management
The goal of systolic blood pressure is <130 mm Hg. All
participants with a diagnosis of hypertension
or whose systolic blood pressure consistently exceeds 130 mmHg will
be prescribed anti-hypertensive
therapy as needed.
The overall goal of therapy for hypertension is to provide maximum
protection against cardiovascular
complications with minimal side effects. Since all participants in
this trial have coronary artery disease
and have symptoms or inducible ischemia, initial therapy should be
a beta-blocker. If the goal of blood
pressure is not reached, the next step is usually the addition of
an ACE inhibitor (ACE-I) or angiotensin
receptor blocker (ARB). An ACE-I or ARB should be administered to
all hypertensive participants with
diabetes, left ventricular systolic dysfunction. In general, all
participants should be on a beta-blocker
and an ACE-I or ARB prior to the addition of a diuretic or calcium
channel blocker. If there are
contraindications to use, side effects, or blood pressure is not
controlled after following the hypertension
algorithm, the site PI should discuss therapeutic options with the
participant’s personal physician.
13.1.5 Diabetes Management
Study investigators will advise the cardiologists, endocrinologists
and internal medicine doctors
regarding the level and intensity of care of hypertension,
diabetes, and lipids as well as of all other risk
TUXEDO-2-INDIA Page 30 of 40
factors. The medical management of diabetes in the study patients
will be carried out according to the
American Diabetes Association (ADA) guidelines for the treatment of
the diabetic with coronary artery
disease. At the scheduled patients’ visits to the study site, the
investigator will review all recent HbA1C
and lipid levels to monitor the degrees of success in risk factor
modification. The target for treatment
will be HB1Ac level is between 7 % to 8%. Use of SGLT2/GLP1
analogues to be encouraged.
HbA1c goals: ADA -Standards of Medical Care In Diabetes -2018
Recommendations:
• A reasonable A1C goal for many nonpregnant adults is ,7% (53
mmol/mol).
• Providers might reasonably suggest more stringent A1C goals (such
as ,6.5% [48 mmol/mol])
for selected individual patients if this can be achieved without
significant hypoglycemia or
other adverse effects of treatment (i.e., polypharmacy).
Appropriate patients might include
those with short duration of diabetes, type 2 diabetes treated with
lifestyle or metformin only,
long life expectancy, or no significant cardiovascular
disease
• Less stringent A1C goals (such as,8% [64mmol/mol])may be
appropriate for patients with a
history of severe hypoglycemia, limited life expectancy, advanced
microvascular or
macrovascular complications, extensive comorbid conditions, or
long-standing diabetes in
whom the goal is difficult to achieve despite diabetes
self-management education,
appropriate glucose monitoring, and effective doses of multiple
glucose-lowering agents
including insulin
13.1.6 Lipid Management
The primary lipid goal is LDL cholesterol ≤55 mg/dL, non-HDL
cholesterol <100 mg/dL if TG >200.
Lipid profiles (total cholesterol, triglycerides, HDL cholesterol,
and LDL cholesterol—preferably
fasting) should be analyzed at baseline, six months, and then at 12
months. An attempt will be made to
coordinate participant follow-up visits at the research clinic so
that they occur in close proximity to
routine visits with their personal physicians when scheduled blood
tests are performed. If lipid tests are
not available within acceptable time windows, the study coordinator
will obtain them or, participants
will be referred to their personal physicians for the tests. If the
participant’s LDL cholesterol was at goal
on the most recent lipid panel, and no change in statin or other
lipid therapy has occurred, it is not
necessary to repeat a lipid panel until the next scheduled
visit.
High-Intensity:
Pitavastatin 2–4 mg
If the LDL goal is not reached after the maximum tolerated dose of
a statin and triglycerides <200
mg/dL addition of one of the following agents should be considered:
ezetimibe, or niacin. If triglycerides
are >500 mg/dL add fenofibrate, omega-3 fatty acids, or
niacin.
TUXEDO-2-INDIA Page 31 of 40
13.1.7 Risk Factor Goals of TUXEDO-2-INDIA
Risk Factor Goal
Systolic Blood pressure Systolic Blood pressure <130 mmHg
LDL cholesterol LDL cholesterol <55 mg/dL
Non-HDL cholesterol <100 mg/dL if TG >200 mg/dL
Diabetes more stringent HbA1c 6.5%
less stringent HbA1c 8%
14.1 GENERAL OVERVIEW OF STUDY COMPLIANCE
Adherence to the study protocol is expected, in accordance with the
protocol agreement executed by the
principal investigator and sponsor, and Institutional Research
Board (IRB)/Institutional Ethics
Committee (IEC) approval.
Protocol violations must be dealt with in line with ICH Guideline
for Good Clinical Practice, local
regulations, IRB /IEC requirements, and the sponsor reporting
prerequisites.
Protocol violations are deviations from the study protocol
that:
Increase the risk to a subject
Decrease the benefit to a subject
Affect subjects’ rights, safety, and/or welfare
Affect the integrity of the resultant data
Protocol violations include, but are not limited to the
following:
Enrolment of an ineligible patient
Informed consent not obtained prior to performing any study related
procedure
Protocol specified procedures not completed as required
Breach of participant confidentiality
Protocol violations may be:
Implemented in order to eliminate an immediate hazard to
subjects
Unanticipated
In the event that a protocol violation occurs, Protocol Violation
Reporting Requirements must be
adhered.?
IRB/IEC Requirements
Protocol violation reporting requirements vary by IRB/IEC. Many
have defined minimal requirements
for a protocol violation that must be met before that violation is
deemed reportable. Site staff must
familiarize themselves with the policies and reporting requirements
for the IRB /IEC on record.
TUXEDO-2-INDIA Page 32 of 40
Sponsor Requirements
The Sponsor is to be notified of all protocol violations, whether
or not they are reportable to the
IRB/IEC, or regulatory authorities. Protocol violations will be
reported to the Sponsor in the following
way.
• Anticipated protocol violations must receive approval of the
sponsor prior to the
implementation of any such violation, except where violation to the
protocol is necessary to
eliminate an immediate hazard(s) to subjects.
• Protocol violations implemented to eliminate an immediate
hazard(s) to subjects will be
reported to the Sponsor soon after the violation occurs.
• Unanticipated protocol violations will be reported soon after the
violation occurs.
• Protocol violations will be reported on the Protocol Violation
Reporting Form and submitted to
the Sponsor and CRO. However, when violations are reportable to the
IRB/IEC, sites are
permitted to submit IRB/IEC correspondence to the Sponsor and CRO
in lieu of the Protocol
Violation Reporting Form. If the Sponsor requires additional
information, the site will be
notified.
• Upon Sponsor and CRO review, the Protocol Violation Reporting
Form will be returned to the
site. The CRO will follow-up on any corrective action necessary for
the protocol violation in
question or to prevent similar violations.
• All protocol violations will be recorded on a log, either the
Protocol Violation Log provided.
The violation log is to be kept in the Investigator Site File and
submitted annually to IRB/IEC
with progress reports or as part of continuing review.
15. SERIOUS ADVERSE EVENT (SAE)
Adverse event that
a) led to death,
b) led to serious deterioration in the health of the subject, that
either resulted in
1) a life-threatening illness or injury, or
2) a permanent impairment of a body structure or a body
function,
or
4) medical or surgical intervention to prevent life-threatening
illness or injury or permanent
impairment to a body structure or a body function,
c) led to fetal distress, fetal death or a congenital abnormality
or birth defect
NOTE 1: This includes device deficiencies that might have led to a
serious adverse event if
a) suitable action had not been taken or
b) intervention had not been made or
c) if circumstances had been less fortunate.
These are handled under the SAE reporting system.
NOTE 2: A planned hospitalization for pre-existing condition, or a
procedure required by the Clinical
Investigation Plan, without a serious deterioration in health, is
not considered to be a serious adverse
event.
15.1 SAE reporting timeline and process
All SAEs should be reported within 48 hours of knowledge of the
event. In case the SAE is one of the
endpoints, it should be entered in the eCRF within 48 hours of
knowledge of the event.
All SAE will be notified in the SAE FORM which is to be filled by
the site team and share it with the
ethics committee, Sponsor and JSS team.
*Reporting of serious adverse event to regulatory authority is not
required for this study.
TUXEDO-2-INDIA Page 33 of 40
15.2 Bleeding
In case of any bleeding, report in the bleeding form as per the
BARC classification:
Type 0 no evidence of bleeding.
Type 1 bleeding that is not actionable and does not cause the
patient to seek unscheduled
performance of studies, hospitalization, or treatment by a
healthcare professional.
Examples include, but are not limited to, bruising, hematoma,
nosebleeds, or
hemorrhoidal bleeding for which the patient does not seek medical
attention. Type 1
bleeding may include episodes that lead to discontinuation of
medications by the patient
because of bleeding without visiting a healthcare provider.
Type 2 any clinically overt sign of hemorrhage (eg, more bleeding
than would be expected for a
clinical circumstance, including bleeding found by imaging alone)
that is actionable but
does not meet criteria for type 3, type 4 (CABG-related), or type 5
(fatal bleeding) BARC
bleeding. The bleeding must require diagnostic studies,
hospitalization, or treatment by a
healthcare professional.
In particular, the bleeding must meet at least one of the following
criteria:
First, it requires intervention, defined as a healthcare
professional–guided medical
treatment or percutaneous intervention to stop or treat bleeding,
including temporarily or
permanently discontinuing a medication or study drug. Examples
include, but are not
limited to, coiling, compression, use of reversal agents (eg,
vitamin K, protamine), local
injections to reduce oozing, or a temporary/permanent cessation of
antiplatelet,
antithrombin, or fibrinolytic therapy.
Second, the bleeding leads to hospitalization or an increased level
of care, defined as
leading to or prolonging hospitalization or transfer to a hospital
unit capable of providing
a higher level of care.
Or third, the bleeding prompts evaluation, defined as leading to an
unscheduled visit to a
healthcare professional resulting in diagnostic testing (laboratory
or imaging).
Examples include, but are not limited to, hematocrit testing,
hemoccult testing,
endoscopy, colonoscopy, computed tomography scanning, or
urinalysis. A visit or phone
call to a healthcare professional during which neither testing nor
treatment is undertaken
does not constitute type 2 bleeding.
Type 3 clinical, laboratory, and/or imaging evidence of bleeding
with specific healthcare
provider responses, as listed below:
Type 3a bleeding:
o Any transfusion with overt bleeding
o Overt bleeding plus hemoglobin drop ≥3 to <5 g/dL (provided
hemoglobin drop
is related to bleeding). Hemoglobin drop should be corrected for
intracurrent
transfusion in which 1 U packed red blood cells or 1 U whole blood
would be
expected to increase hemoglobin by 1 g/dL.
Type 3b bleeding:
o Overt bleeding plus hemoglobin drop ≥5 g/dL (provided hemoglobin
drop is
related to bleed). Hemoglobin drop should be corrected for
intracurrent
transfusion in which 1 U packed red blood cells or 1 U whole blood
would be
expected to increase hemoglobin by 1 g/dL.
o Cardiac tamponade
dental/nasal/skin/hemorrhoid)
o Bleeding requiring intravenous vasoactive drugs
Type 3c bleeding: Intraocular bleed compromising vision
Type 4 Coronary Artery Bypass Graft–related bleeding
o Perioperative intracranial bleeding within 48 hours
o Reoperation after closure of sternotomy for the purpose of
controlling bleeding
o Transfusion of ≥5 U whole blood or packed red blood cells within
a 48-hour
period (only allogenic transfusions are considered transfusions for
CABG-related
bleeds)
o Chest tube output ≥2 L within a 24-hour period
Notes: If a CABG-related bleed is not adjudicated as at least a
type 3 severity event, it
will be classified as not a bleeding event. If a bleeding event
occurs with a clear temporal
relationship to CABG (ie, within a 48-hour time frame) but does not
meet type 4 severity
criteria, it will be classified as not a bleeding event.
Type 5 Fatal bleeding
Type 5a: Probable fatal bleeding is bleeding that is clinically
suspicious as the cause of
death, but the bleeding is not directly observed and there is no
autopsy or confirmatory
imaging.
type 5b: Definite fatal bleeding is bleeding that is directly
observed (by either clinical
specimen [blood, emesis, stool, etc] or imaging) or confirmed on
autopsy.
16. MONITORING
• the rights and well-being of human subjects are protected,
• the reported trial data are accurate, complete and verifiable
from source documents,
• the conduct of the trial is in compliance with the currently
approved protocol/amendments,
with GCP, and with the applicable regulatory requirements.
Monitoring assessments will verify study activities in the
following categories:
Protocol compliance
Sponsor or CRO representatives will conduct on-site monitoring.
Frequency of monitoring visits will
depend on the number of participants enrolled at the site and
events reported. The Sponsor or CRO may
also conduct remote site monitoring by requesting medical records,
source notes, lab reports, etc. Sites
will scan the requested documents to the sponsor. All participants’
names and identifiers will be redacted
and replaced with unique Participant ID.
17. DATA COLLECTION AND EDC SYSTEM
Please refer to the Operation manual for EDC
TUXEDO-2-INDIA Page 35 of 40
18. SITE CLOSURE
At site closure and/or study completion, the Sponsor or managing
CRO will inform sites of close-out
procedures and timelines for final data clean-up, data base lock
and site close-out as soon as possible so
sites can start planning.
Close-out procedures include:
• Notification of local IRB/EC of site close-out, in accordance
with the IRB/EC requirements.
• Submission of study essential documents (e.g. study staff log,
final participant list) as directed
by the Sponsor or CRO.
• Site PI must ensure that all relevant study site personnel fill
out the Study Staff Log.
• Reconciliation of study payments.
• Completion of any data entry and resolution of any data queries;
obtain electronic signature of
PI on final eCRFs.
• Storage of study documents; sites are expected to retain study
files for at least 1 years or as per
any applicable guidelines of the country once after confirmation by
the Sponsor that the study
is officially closed.
• Reconciliation of all study essential documents with those on
file at the Sponsor or managing
CRO
• Site Closeout Visits.
If the Investigator or site IRB/EC terminates the trial conduct at
site prior to study closure
The investigator should inform the institution, where applicable,
and the Sponsor and or managing CRO,
and should provide a detailed written explanation for the
termination. The Sponsor or CRO will contact
you to plan site closeout.
The Sponsor or managing CRO may elect to terminate the trial
conduct at a site prior to study closure;
the Sponsor or CRO will contact you to plan site closeout.
Sites will receive final notification from the Sponsor or managing
CRO when all items have been
reconciled and tasks complete.
After database lock, a copy of the site-specific participant eCRF
Data will be sent to sites for record
Maintenance and archiving for specified period as per regulatory
guidelines
19. STUDY COMPLETION
At study completion, or close-out, certain procedures must be
undertaken to fulfil administrative, data
and any other requirements after last randomized participant
follow-up has been completed, and are as
follows:
Communication with IRBs/ECs in accordance with the IRB/EC
requirements
Participant notification of study completion
Planning for dissemination of results (at participant/community
level and elsewhere)
Preparation of manuscripts
Site closeout visits
Study record retention
20. REGULATORY COMPLIANCE
20.1 International Conference on Harmonization and Good Clinical
Practice
The TUXEDO-2 study will be conducted in compliance with the
International Conference on
Harmonisation’s (ICH) Good Clinical Practice E6 Consolidated
Guidance (R2) 2016, ICMR Guidelines
TUXEDO-2-INDIA Page 36 of 40
2017 and in accordance with applicable regulatory requirements.
Investigators and study coordinators
should understand their commitments set forth in these regulations
and standards.
20.2 INSTITUTIONAL REVIEW BOARD/ETHIC COMMITTEE APPROVALS
The study protocol, informed consent form and recruitment materials
must be approved by the
responsible Institutional Review Board/Ethics Committee (IRB/IEC).
The responsible IRBs/IECs must
review and approve all required study related documentation prior
to the initiation of study. Thereafter,
all studies must undergo continuing review and be approved at least
annually, even if less frequent
reviews are required locally. Protocol amendments generated during
the study must be approved by the
IRBs/IECs prior to their implementation.
ICH GCP guidelines specify that a clinical research site is
required to submit the study documents to
their IRB/IEC when obtaining initial and continuing review of
research involving human subjects. Some
IRBs/IECs may require additional documentation in support of their
reviews (e.g., copies of Case Report
Forms). Sites must communicate with IRBs/IECs to ascertain what
documentation is required and site
staff must comply with all the IRB/IEC requirements.
Site staff must maintain documentation of all submissions and
approvals from all responsible
IRBs/IECs, including any other IRB/IEC correspondence, in their
Investigator Site Master File. It is a
requirement for all IRB/IEC approval documentation to be labelled
with the full protocol title, version
number, and/or version date. Study sites are encouraged to request
that IRBs/ECs note the effective and
expiration dates of all approvals. It is recommended that IRB/EC
submission letter include a complete
listing of all study documents that approval is being requested
for, including version number and date.
An annual progress report must be submitted and continuing review
and approval is required at least
annually.
20.3 INVESTIGATOR SITE FILE
Essential documents should be kept in a specific Investigator Site
File (ISF), or regulatory binder, to
maintain regulatory compliance and adhere to high standards of
practice in the conduct of research
involving human subjects. A suggested ISF outline, or regulatory
binder table of contents, is provided
in the table below.
• A dedicated individual(s) at the site should be responsible for
maintaining the binder.
This person should be the contact person to ensure that all IEC
correspondence and
documents are received/filed in a timely manner
• Keep the regulatory binder current and up-to-date
• Older versions of study documents should also be retained and
filed in reverse
chronological order.
• Documents must be stored in a safe and secure location, but
accessible to study staff at
all times. Participant-specific documentation and information, such
as signed consent
forms, test results, should be maintained separately in at a secure
location.
• If any documents are filed separately from the Investigator Site
File, then a note should
be made in the study file detailing where the document is
stored.
Documents needed to be filed: -
o Protocol and its amendments
o Informed consent documents and amendments as applicable
o Participant recruitment and educational materials
o IRB/IEC approvals and correspondence
o Curriculum Vitae (CV)
o Study logs
o Relevant communications
21. PUBLICATION POLICY
The Steering Committee and investigators are committed to the
publication and wide spread
dissemination of the results of the study. Data from this study
will not be withheld regardless of the
findings.
Primary and secondary reports of study findings will be published
in peer reviewed journals. Proposals
for presentations and publications incorporating data from
participants involved in the TUXEDO-2
study must be submitted for review by the Steering Committee and
investigators. The primary
publication will be authored by the study’s writing committee. No
site is permitted to present or publish
data obtained during the conduct of this study without prior
approval from the Steering Committee and
investigators. Authorship for TUXEDO-2 related publications will be
determined by the Steering
Committee and investigators taking into account contribution to the
study and the relevant analyses.
This study represents a joint effort between the SPONSOR, steering
committee members and
Investigators, and as such, the parties agree that the
recommendation of any party concerning
manuscripts or text shall be taken into consideration in the
preparation of final scientific documents for
publication or presentation.
The names of the top enrolling investigators will be included in
the publication of the TUXEDO-2
INDIA study result. All proposed publications and presentations by
Investigators resulting from or
relating to the study must be submitted to the Leadership and
Steering Committee for review and
approval prior to submission for publication or presentation.
22. OTHER DEFINITIONS
Type A Lesions (High Success, >85%; Low Risk)
* discrete (< 10 mm length) * Little or no calcification
*Concentric * Less than totally occlusive
*Readily accessible * Not ostial in location
*Nonangulated segment, < 45 *No major branch involvement
*Smooth contour *Absence of thrombus
Type B Lesions* (Moderate Success, 60-85%; Moderate risk)
*Tubular (10-20 mm length) * Moderate-to-heavy calcification
*Eccentric *Total occlusions < 3 mo old
*Moderate tortuosity of proximal segment * Ostial in location
*Moderately angulated segment, > 45< 90 *Bifurcation lesions
requiring double guidewires
*Irregular contour *Some thrombus present
* Type B1 lesions: One adverse characteristic
* Type B2 lesions: Two adverse characteristics
Type C Lesions (Low Success, <60%; High Risk)
* Diffuse (> 20 mm length) * Total occlusions > 3 months
old
* Excessi