manual of operation t u x e in a diabetic population 2

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
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.
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.
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
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
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
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.
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.
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
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.
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
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.
• 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.
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)
• 12-lead electrocardiogram
• Current Cardiac and Diabetic medications
• Safety assessment
• Laboratory assessments (HbA1c, lipid profile, electrolytes (Na, K, Cl), CBC)
• Laboratory assessments (HbA1c, lipid profile, S.creatinine and electrolytes (Na, K, Cl), CBC)
36 months (±30 days)/48 month (±30 days)/60 month (±30 days)
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.
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 antiplatelet 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
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.
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.
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.
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
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
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