| CTRI Number |
CTRI/2017/08/009566 [Registered on: 31/08/2017] Trial Registered Retrospectively |
| Last Modified On: |
30/08/2017 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Drug
Preventive |
| Study Design |
Randomized, Parallel Group, Active Controlled Trial |
Public Title of Study
Modification(s)
|
Investigation of effect of clot preventing drugs such as Rivaroxaban, Vitamin K Antagonists and Aspirin on prevention of stroke in patients having Rheumatic Heart Disease along with irregularity of heart rhythm (Atrial Fibrillation). |
|
Scientific Title of Study
|
INVestIgation of rheumatiC AF Treatment Using vitamin K antagonists, rivaroxaban or aspirin Studies |
|
Secondary IDs if Any
|
| Secondary ID |
Registry |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Dr G Krthikeyan |
| Address |
Room. No. 24, 7th Floor, Cardio-Thoracic Sciences Center, AIIMS, New Dlehi
New Delhi
DELHI
110029
India |
| Phone |
011-26594464 |
| Fax |
|
| Email |
karthik2010@gmail.com |
|
Details Contact Person
Scientific Query
|
| Name |
Dr G Krthikeyan |
| Address |
Room. No. 24, 7th Floor, Cardio-Thoracic Sciences Center, AIIMS, New Dlehi
New Delhi
DELHI
110029
India |
| Phone |
011-26594464 |
| Fax |
|
| Email |
karthik2010@gmail.com |
|
Details Contact Person
Public Query
|
| Name |
Dr G Krthikeyan |
| Address |
Room. No. 24, 7th Floor, Cardio-Thoracic Sciences Center, AIIMS, New Dlehi
New Delhi
DELHI
110029
India |
| Phone |
011-26594464 |
| Fax |
|
| Email |
karthik2010@gmail.com |
|
Source of Monetary or Material Support
Modification(s)
|
| Population Health Research Institute (PHRI)
Hamilton General Hospital Campus, DBCVSRI
237 Barton Street East
Hamilton, Ontario, Canada L8L 2X2 |
|
|
Primary Sponsor
|
| Name |
Population Health Research Institute |
| Address |
INVICTUS Trials Project Office
Population Health Research Institute (PHRI)
Hamilton General Hospital Campus, DBCVSRI
237 Barton Street East
Hamilton, Ontario, Canada |
| Type of Sponsor |
Government medical college |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
Angola
Botswana
Brazil
Cameroon
China
Egypt
Ethiopia
Guatemala
India
Kazakhstan
Kenya
Kyrgyzstan
Mauritius
Mozambique
Namibia
Nigeria
Pakistan
Paraguay
Philippines
Rwanda
South Africa
Sudan
Uganda
Zambia
Zimbabwe |
Sites of Study
Modification(s)
|
| No of Sites = 14 |
| Contact Person |
Name of Site |
Site Address |
Phone/Fax/Email |
| Dr G Karthikeyan |
All India Institute of Medical Sciences |
Room No. 24, 7th Floor, Department of Cardiology,
Cardio-Thoracic Sciences Center
New Delhi
|
011-26594464
karthik2010@gmail.com |
| Dr Paul V George |
CHRISTIAN MEDICAL COLLEGE |
Department of Cardiology
Vellore
|
04162282631
drpaulcmc@gmail.com |
| Dr Ashish Chouhan |
Command Hospital (Air Force) |
Department of Cardiology
Bangalore
|
9871137768
drashishalini@gmail.com |
| Dr Ranjit Nath |
Dr Ram Manohar Lohia Hospital and PGIMER |
Department of Cardiology
New Delhi
|
01123404531
ranjitknath@yahoo.com |
| Dr Vivek Chaturvedi |
Govind Ballabh Pant Hospital |
Department of Cardiology
New Delhi
|
011232342425124
chaturvedimd@gmail.com |
| Dr S Anandaraja |
INDIRA GANDHI GOVERNMENT GENERAL HOSPITAL AND POSTGRADUATE INSTITUTE |
Department of Cardiology
Pondicherry
|
9488084379
s.anandaraja@gmail.com |
| Dr Sanjeev Asotra |
Indira Gandhi Medical College |
Department of Cardiology
Shimla
|
01772883408
dr.sanjeev00@gmail.com |
| Dr Santhosh Satheesh |
Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) |
Department of Cardiology
Pondicherry
|
914132297015
drsanthoshsatheesh@gmail.com |
| Dr Prafulla Kerkar |
KEM and Seth GS Medical College |
Department of Cardiology
Mumbai
|
02224107595
prafullakerkar@rediffmail.com |
| Dr Parag Barwad |
Post Graduate Institute of Medical Education and Research |
Department of Cardiology
Chandigarh
|
9013472103
paragaims@gmail.com |
| Dr Sudeep Kumar |
Sanjay Gandhi Post Graduate Institute of Medical Sciences |
Department of Cardiology
Lucknow
|
05222495198
sudeepkum@yahoo.com |
| Dr Chandra Bhan Meena |
SawaiMan Singh Medical College |
Department of Cardiology
Jaipur
|
9414250934
drcbhan@gmail.com |
| Dr L Shridhar Shastry |
Sri Jayadeva Institute of Cardiovascular Sciences and Research |
Department of Cardiology
Bangalore
|
080-22977395
crc.jayadeva@gmail.com |
| PRAVAT KUMAR DASH |
SRI SATHYA SAI INSTITUTE OF HIGHER MEDICAL SCIENCES |
Department of Cardiology
Bangalore
|
9448517990
drdashpk@rediffmail.com |
|
Details of Ethics Committee
Modification(s)
|
| No of Ethics Committees= 14 |
| Name of Committee |
Approval Status |
| Ethics Committee , Indira Gandhi Medical College, Shimla |
Submittted/Under Review |
| Ethics Committee , SMS Medical College & Attached Hospital |
Submittted/Under Review |
| Ethics Committee Command Hospital (Air Force) |
Submittted/Under Review |
| Ethics Committee Silver, CMC Vellore |
Submittted/Under Review |
| Institute Ethics Committee (Human Studies) IGMC & RI |
Submittted/Under Review |
| Institute Ethics Committee All India Institute of Medical Sciences |
Approved |
| Institute Ethics Committee, Dr. RML Hospital |
Approved |
| Institutional Ethics Committee |
Approved |
| Institutional Ethics Committee I & II, Seth GS Medical College and KEM Hospital |
Submittted/Under Review |
| Institutional Ethics Committee PGI, Chandigarh |
Approved |
| Institutional Ethics committee, JIPMER |
Submittted/Under Review |
| Institutional Ethics Committee, MAMC |
Approved |
| King Georges Medical University, Institutional Ethics Committee |
Approved |
| SriJayadeva Institute Ethics Committee |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
Rheumatic Valvular Heart Disease with either atrial fibrillation or high risk of stroke. |
|
Intervention / Comparator Agent
Modification(s)
|
| Type |
Name |
Details |
| Comparator Agent |
Aspirin |
Oral Aspirin 75 to 100 mg once daily (in Superiority trial) for the duration of the study (four years) |
| Intervention |
Rivaroxaban |
Oral Rivaroxaban 20 mg daily (in Non-inferiority Trial) for the duration of the study (four years),
Oral Rivaroxaban 15 mg daily (in Superiority Trial) for the duration of the study (four years) |
| Comparator Agent |
Vitamin K Antagonists (such as Warfarin and Acenocoumarol) |
Once daily Oral Vitamin K Antagonists for the duration of the study (four years). The dose varies from patient to patient and time to time for the same patient to achieve PT INR range 2 to 3 |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
80.00 Year(s) |
| Gender |
Both |
| Details |
Non-Inferiority Trial:
1. RVHD diagnosed by echocardiography at any time prior to enrollment
2. Age ≥18
3. Increased risk of stroke by any of the following
a) CHA2DS2-VASc score ≥ 2 OR
b) Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR
c) Left atrial spontaneous echo contrast OR
d) Left atrial thrombus
4. Heart Rhythm
a) AF or Flutter should be documented on baseline 12-lead ECG, or on a
previous 12-lead ECG, Holter monitor, in-hospital ECG rhythm strip or
Pacemaker or ICD electrogram.
Superiority Trial
1. RVHD diagnosed by echocardiography at any time prior to enrollment
2. Age ≥18
3. Increased risk of stroke by any of the following
a) CHA2DS2-VASc score ≥ 2 OR
b) Moderate/Severe mitral stenosis with valve area ≤2.0 cm2 OR
c) Left atrial spontaneous echo contrast OR
d) Left atrial thrombus
4. Heart Rhythm
a) AF or Flutter and unsuitable for VKA therapy. (AF or Flutter should be
documented on baseline 12-lead ECG, or on a previous 12-lead ECG,
Holter monitor, in-hospital ECG rhythm strip or Pacemaker or ICD
electrogram) OR
b) In the absence of AF or Flutter, patients would be eligible in the presence
of any one of the following:
a. Left atrial enlargement ≥5.5 cm OR
b. Left atrial spontaneous echo contrast OR
c. Left atrial thrombus OR
d. Frequent ectopic atrial activity (>1000/24 hours) on Holter monitoring |
|
| ExclusionCriteria |
| Details |
For both Non-inferiority and Superiority trials:
1. Refusal to consent
2. Actively involved in any study that would compromise the protocol of
INVICTUS Trial
3. Severe co-morbid condition with life expectancy < 1 year
4. Other serious condition(s) or logistic factors likely to interfere with study
participation or with the ability to complete the trial, as appropriate to country
or region.
5. Likely to have valve replacement surgery within 6 months
6. Mechanical valve prosthesis or other condition requiring treatment with VKAs.
Patients with deep vein thrombosis or recent pulmonary embolism can be
enrolled where both VKAs and rivaroxaban are approved.
7. Contraindication to the study medication of the trial
a. Allergy to rivaroxaban
b. Allergy to VKAs ( non-inferiority trial)
c. Allergy to aspirin ( superiority trial)
8. Severe renal insufficiency with an calculated creatinine clearance (Cockcroft-
Gault) < 15 ml/min
9. Serious bleeding in the past six months or at high risk for bleeding
10. Moderate to severe hepatic impairment
11. Ongoing need for dual antiplatelet therapy (patients with on-going aspirin
therapy ≤100 mg per day are not excluded).
12. Ongoing need for dual strong inhibitors of CYP-3a4 or p-glycoprotein
inhibitor.
13. Received an investigational drug in the past 30 days
14. Patients considered unsuitable for trial inclusion because of unwillingness to
attend follow up visits
15. Women who are pregnant and/or breastfeeding
16. Women of child bearing age who do not use an effective form of birth control. |
|
|
Method of Generating Random Sequence
|
Computer generated randomization |
|
Method of Concealment
|
Centralized |
|
Blinding/Masking
|
Open Label |
|
Primary Outcome
|
| Outcome |
TimePoints |
1) Stroke(ischemic, hemorrhagic or undetermined type)
2) Systemic embolism |
At first one month follow-up, and then every at six month follow-up there after , till four years from randomization. |
|
|
Secondary Outcome
|
| Outcome |
TimePoints |
Myocardial infarction
- Hospitalization
- Vascular death
- Total Death
- Composite of stroke, myocardial infarction, systemic embolism, vascular death |
At first one month follow-up, and then every at six month follow-up there after , till four years from randomization. |
Safety Outcomes:
Major Bleeding (ISTH definition)
Minor bleeding |
At first one month follow-up, and then every at six month follow-up there after , till four years from randomization. |
|
Target Sample Size
Modification(s)
|
Total Sample Size="6500"
Sample Size from India="1500" |
|
Phase of Trial
|
Phase 4 |
|
Date of First Enrollment (India)
|
01/07/2016 |
| Date of First Enrollment (Global) |
01/07/2016 |
|
Estimated Duration of Trial
|
Years="4"
Months="0"
Days="0" |
Recruitment Status of Trial (Global)
Modification(s)
|
Open to Recruitment |
| Recruitment Status of Trial (India) |
Open to Recruitment |
|
Publication Details
|
|
|
Brief Summary
|
The overall program objective of INVICTUS is a comprehensive evaluation of Rheumatic Valvular Heart Disease ( RVHD), Atrial Fibrillation (AF) and stroke. It includes three components 1. A registry of RVHD 2. A randomized clinical trial of rivaroxaban versus Vitamin K antagonist therapy (VKA) to establish the non-inferiority and potential superiority of rivaroxaban compared to VKA; and 3. A superiority trial to compare rivaroxaban to aspirin in patients who are unsuitable for VKA therapy or who do not have AF/flutter but who do have other risk factors.
Statement of hypothesis.
1) Non-Inferiority Trial of rivaroxaban versus VKA: This trial will test the hypothesis that rivaroxaban is non-inferior to VKAs for the prevention of stroke or systemic embolism in patients with AF/flutter and RVHD; and is potentially superior to VKAs.
2) Superiority Trial of rivaroxaban versus aspirin: This trial will test the hypothesis that rivaroxaban is superior to aspirin for the prevention of the composite of stroke or systemic embolism in patients with RVHD with AF or flutter who are unsuitable for VKA therapy, or in patients with RVHD without AF or Flutter with at least one of the following: (1) Left atrial enlargement ≥ 5.5 cm, OR (2) Left atrial spontaneous echo contrast OR (3) Left atrial thrombus OR (4) Frequent ectopic atrial activity (>1000/24 hours) on Holter ECG. |
